Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools

ABSTRACT

A compound of formula: in which: 
     Ar represents a pyrid-2-yl or a phenyl which is unsubstituted or substituted by a halogen, a methyl or a (C 1  -C 4 )alkoxy; 
     R 1  represents a methyl group; 
     R 11  represents hydrogen; 
     or R 1  and R 11  together represent a --(CH 2 ) 3  -- group; 
     R 2  represents a hydroxyl; a (C 1  -C 7 )alkoxy; a (C 1  -C 7 )acyloxy; a cyano; an --NR 6  R 7  group; an --NR 3  COR 4  group; an --NR 3  COOR 8  group; an --NR 3  SO 2  R 9  group; an --NR 3  CONR 10  R 12  group; a (C 1  -C 7 )acyl group; a (C 1  -C 7 )alkoxycarbonyl; a --CONR 10  R 12  group; a --CH 2  OH group; a (C 1  -C 7 )alkoxymethyl; a (C 1  -C 7 )acyloxymethyl; a (C 1  -C 7 )alkylaminocarbonyloxymethyl; a --CH 2  NR 13  R 14  group; a --CH 2  NR 3  COR 4  group; a --CH 2  NR 3  COOR 8  group; a --CH 2  NR 3  SO 2  R 9  group; a --CH 2  NR 3  CONR 10  R 12  group; or R 2  constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; 
     or Ar and R 2 , together with the carbon atom to which they are attached, constitute a group of formula: ##STR1## Application: NK 3  antagonists

This application is a division of application Ser. No. 08/405,833, filedMar. 17, 1995 now abandoned.

The subject of the present invention is new compounds which areselective antagonists of the human NK₃ receptor and their use for thepreparation of medicinal products useful in the treatment of psychiatricdiseases, of diseases of psychosomatic origin, of hypertension and,generally, of any central or peripheral pathology in which neurokinin Band the NK₃ receptor are involved in interneuronal regulation.

During the past few years, many research studies have been carried outon tachykinins and their receptors. Tachykinins are distributed both inthe central nervous system and in the peripheral nervous system. Thetachykinin receptors have been recognized and are classified into threetypes: NK₁, NK₂, NK₃. Substance P (SP) is the endogenous ligand for theNK₁ receptors, neurokinin A (NK_(A)) that for the NK₂ receptors andneurokinin B (NK_(B)) that for the NK₃ receptors.

The NK₁, NK₂, NK₃ receptors have been identified in various species.Thus, the NK₃ receptors have been identified in guinea pigs, rats,monkeys (Br. J. Pharmacol., 1990, 99, 767-773; Neurochem. Int., 1991,18, 149-165); more recently, they were also identified in man (FEBSLetters, 1992, 299 (1), 90-95).

A recent review by C. A. Maggi et al. presents a summary of the findingson the tachykinin receptors and their antagonists and describes thepharmacological studies and the applications on human therapy (J.Autonomic Pharmacol., 1993, 13, 23-93).

Among the specific antagonists of the NK₁ receptor, there may bementioned the following nonpeptide compounds: CP-96345 (J. Med. Chem.,1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88,10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

For the NK₂ receptor, a selective nonpeptide antagonist, SR 48968 hasbeen described in detail (Life Sci., 1992, 50, PL101-PL106).

As regards the NK₃ receptor, some nonpeptide compounds, antagonists forAngiotensin II, have been described, up until now, as having affinityfor rat and guinea pig brain NK₃ receptor; this affinity is very low andcorresponds to an inhibition constant Ki of the order of 10⁻⁵ M (FASEBJ., 1993, 7 (4), A 710, 4104). A peptide antagonist Trp⁷, Ala⁸ !NKA,weakly specific for rat NK₃ receptor has also been described (J.Autonomic Pharmacol., 1993, 13, 23-93).

In Patent Application EP 512901, it is indicated that 5-2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl!-5-(3,4-dichlorophenyl)-1-benzylpiperid-2-onehydrochloride, called hereinafter compound A, antagonizes the binding ofeledoisin with a Ki of 200 nanomolar, eledoisin being a peptide ofbatrachian origin equivalent to neurokinin B.

Patent Application EP 474561 describes neurokinin antagonists, moreparticularly NK₁ or NK₂ receptor antagonists; in particular thisapplication describes N-methyl-N-2-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenylpiperid-1-yl)pentyl!benzamidehydrochloride.

None of the peptide or nonpeptide compounds known up until now have ahigh affinity for the human NK₃ receptor.

Pharmacological studies of the peptide and nonpeptide antagonists of theNK₁ and NK₂ receptors have shown that their affinities for thesereceptors as well as their pharmacological activities were very highly afunction of the species, most probably as a result of small differencesin the aminoacid sequences, thereby inducing very fine structuralvariations in these receptors from one species to another (J. AutonomicPharmacol., 1993, 13, 23-93). Some experimental data, confirmed by thepharmacological characterization of the compounds which are the subjectof the present invention, appear to indicate that a comparable situationexists for the NK₃ receptor. In particular, human NK₃ receptor isdifferent from rat NK₃ receptor.

Nonpeptide compounds have now been found which have a very high affinityfor the human NK₃ receptor and a high specificity for said receptor.These compounds can be used for the preparation of medicinal productswhich are useful in the treatment of psychiatric diseases or of diseasesof psychosomatic origin and of all central or peripheral diseases inwhich neurokinin B and the NK₃ receptor are involved in interneuronalregulation.

Very high affinity for the human NK₃ receptor is understood to mean anaffinity characterized by an inhibition constant Ki which is generallyless than 5.10⁻⁹ M.

In studies on the binding of a ligand, the inhibition constant Ki isdefined by the Cheng-Prusoff equation (in Receptor Binding in DrugResearch, eds. R. A. O'BRIEN. Marcel Dekker, New York, 1986): ##EQU1##L!: ligand concentration Kd: dissociation constant of the ligand,

IC₅₀ : concentration which inhibits 50% of the ligand binding.

By high specificity for the human NK₃ receptor, it is understood thatthe inhibition constant (Ki) for the human NK₃ receptor is generally atleast 100 times lower than the inhibition constant (Ki) for the NK₂receptor or than that for the NK₁ receptor of different species.

Disease of psychosomatic origin designates diseases having their originin the central nervous system (CNS) and pathological consequences at theperipheral level.

Thus, according to one of its aspects, the subject of the presentinvention is compounds of formula: ##STR2## in which: Ar represents apyrid-2-yl or a phenyl which is unsubstituted or substituted by ahalogen, a methyl or a (C₁ -C₄)alkoxy;

R₁ represents the methyl group;

R₁₁ represents hydrogen;

or R₁ and R₁₁ together represent a --(CH₂)₃ -- group;

R₂ represents a hydroxyl; a (C₁ -C₇)alkoxy; a (C₁ -C₇)acyloxy; a cyano;an --NR₆ R₇ group; an --NR₃ COR₄ group; an --NR₃ COOR₈ group; an --NR₃SO₂ R₉ group; an --NR₃ CONR₁₀ R₁₂ group; a (C₁ -C₇)acyl group; a (C₁-C₇)alkoxycarbonyl; a --CONR₁₀ R₁₂ group; a --CH₂ OH group; a (C₁-C₇)alkoxymethyl; a (C₁ -C₇)acyloxymethyl; a (C₁-C₇)alkylaminocarbonyloxymethyl; a --CH₂ NR₁₃ R₁₄ group; a --CH₂ NR₃COR₄ group; a --CH₂ NR₃ COOR₈ group; a --CH₂ NR₃ SO₂ R₉ group; a --CH₂NR₃ CONR₁₀ R₁₂ group; or R₂ constitutes a double bond between the carbonatom to which it is attached and the adjacent carbon atom of thepiperidine ring;

or Ar and R₂, together with the carbon atom to which they are attached,constitute a group of formula: ##STR3## R₃ represents a hydrogen or a(C₁ -C₄)alkyl; R₄ represents a hydrogen, a (C₁ -C₇)alkyl, a phenyl, abenzyl, a pyridyl or a (C₃ -C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls;

or R₃ and R₄ together represent a (CH₂)_(n) group;

n is 3 or 4;

T represents a methylene, a carbonyl, a --COO-- group, a --CONR₅ --group;

A represents a direct bond, a methylene, an ethylene, a propylene, avinylene;

or -T-A- represents the --SO₂ -- group

Z represents a phenyl which is unsubstituted or substituted one orseveral times by a halogen, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, a nitro;

R₅ represents a hydrogen or a (C₁ -C₄)alkyl;

R₆ and R₇ each represent independently a hydrogen or a (C₁ -C₇)alkyl; R₇can furthermore represent a (C₃ -C₇)cycloalkylmethyl, a benzyl or aphenyl; or R₆ and R₇, together with the nitrogen atom to which they areattached, constitute a heterocycle chosen from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine or perhydroazepine;

R₈ represents a (C₁ -C₇)alkyl or a phenyl;

R₉ represents a (C₁ -C₇)alkyl; an amino which is free or substituted byone or two (C₁ -C₇)alkyls; a phenyl which is unsubstituted orsubstituted once or several times by a substituent chosen from: ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro, an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, the said substituents beingidentical or different;

R₁₀ and R₁₂ each represent independently a hydrogen or a (C₁ -C₇)alkyl;R₁₂ may furthermore represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl; or R₁₀ and R₁₂, together with the nitrogen atom to which theyare attached, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine;

R₁₃ and R₁₄ each represent independently a hydrogen or a (C₁ -C₇)alkyl;R₁₄ may furthermore represent a (C₃ -C₇)cycloalkylmethyl or a benzyl;provided that:

1/ when Ar is a phenyl group, R₂ is a hydroxyl group, T-A-Z is thebenzoyl group, R₁ is different from the methyl group;

2/ when Ar is the phenyl group, R₂ is the --NH--CO--CH₃ group, T-A-Z isthe benzoyl group, R₁ and R₁₁ together do not form the --(CH₂)₃ --group;

3/ when Ar is a phenyl group, R₂ is a hydroxyl group, T-A-Z is the3-methoxybenzyl group, R₁ and R₁₁ together do not form the --(CH₂)₃ --group; as well as their salts.

In the present description, the alkyl groups or the alkoxy groups arestraight or branched; halogen is understood to mean a fluorine,chlorine, bromine or iodine atom, preferably a fluorine, chlorine oriodine atom.

In the present description, acyl is understood to mean a formyl or a (C₁-C₆)alkylcarbonyl.

The salts of the compounds of formula (I) comprise both those withinorganic or organic acids which allow a suitable separation orcrystallization of the compounds of formula (I), such as picric acid oroxalic acid or an optically active acid, for example mandelic orcamphosulfonic acid, and those which form pharmaceutically acceptablesalts.

The pharmaceutically acceptable salts are such as hydrochloride,hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate,methanesulfonate, methyl sulfate, maleate, fumarate,2-naphthalenesulfonate, benzenesulfonate, glycolate, gluconate, citrate,isethionate, para-toluenesulfonate.

The present invention encompasses the compounds of formula (I) either inracemic form or in pure enantiomeric form.

Depending on the meaning of R₁ and R₁₁, the compounds of the inventionbelong to one of the families described below of formulae: ##STR4## inwhich: Ar, R₂, T, A and Z have the meanings given above for (I).

The compounds of formula (I) in which:

Ar represents a pyrid-2-yl or a phenyl which is unsubstituted orsubstituted by a halogen:

R₁ represents a methyl group;

R₁₁ represents hydrogen;

or R₁ and R₁₁ together represent a --(CH₂)₃ -- group;

R₂ represents a hydroxyl, a (C₁ -C₇)alkoxy, an amino, a (C₁ -C₇)acyloxy,an --NR₃ COR₄ group, or R₂ constitutes a double bond between the carbonatom to which it is attached and the adjacent carbon atom of thepiperidine ring;

R₃ represents a hydrogen or a (C₁ -C₄)alkyl;

R₄ represents a hydrogen, a (C₁ -C₇)alkyl, a phenyl, a pyridyl or a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls;

or R₃ and R₄ together represent a --(CH₂)_(n) -- group;

n is 3 or 4;

T represents a methylene, a carbonyl, a --COO-- group, a --CONR₅ --group;

A represents a direct bond, a methylene, an ethylene, a propylene, avinylene;

or -T-A- represents the --SO₂ -- group

Z represents a phenyl which is unsubstituted or substituted once orseveral times by a halogen, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, a nitro;

R₅ represents a hydrogen or a (C₁ -C₄)alkyl; provided that:

1/ when Ar is a phenyl group, R₂ is a hydroxyl group, T-A-Z is thebenzoyl group, R₁ is different from the methyl group;

2/ when Ar is the phenyl group, R₂ is the --NH--CO--CH₃ group, T-A-Z isthe benzoyl group, R₁ and R₁₁ together do not form the --(CH₂)₃ --group;

3/ when Ar is a phenyl group, R₂ is a hydroxyl group, T-A-Z is the3-methoxybenzyl group, R₁ and R₁₁ together do not form the --(CH₂)₃ --group; as well as their salts; are preferred compounds.

The compounds of formula (II) in which R₂ is an acetamido, apropionylamino, a butyrylamino, an isobutyrylamino, anacetyl-N-methylamino, a propionyl-N-methylamino, abutyryl-N-methylamino, an isobutyryl-N-methylamino and T-A-Z is abenzyloxycarbonyl which is unsubstituted or substituted on the phenyl bya chlorine or a nitro are also preferred.

The compounds of formula (III) in which Ar represents a phenyl which isunsubstituted or substituted by a halogen, R₂ represents a (C₁ -C₈)acylamino, an acyl-N-methylamino in which the acyl is in C₁ -C₈, T-A-Zrepresents a benzoyl, are also preferred compounds.

Thus, the following compounds:

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(acetyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-propionylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-propionyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl! piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-butyrylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-butyryl-N-methylamino)-4-phenylpiperidin-1-yl)-propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-isobutyrylamino-)4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-isobutyryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-valerylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-valeryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-isovalerylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-isovaleryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,in the form of racemates or one of their (+) or (-) enantiomers andtheir salts are particularly preferred.

1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(acetyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidinehydrochloride, in optically pure form, preferably in the form of the (+)isomer, is most particularly preferred.

Among the compounds of formula (II), those in which:

either R₂ represents a (C₅ -C₇)alkoxy, a (C₅ -C₇)acyloxy, an --NR₃ COR₄group with R₄ other than (C₁ -C₆)alkyl when R₃ is hydrogen, an --NR₆ R₇group with R₆ and R₇ other than H or (C₁ -C₄)alkyl, an --NR₃ COOR₈group, an --NR₃ SO₂ R₉ group, an --NR₃ CONR₁₀ R₁₂ group, a (C₅ -C₇)acyl,a (C₅ -C₇)alkoxycarbonyl, a --CONR₁₀ R₁₂ group, a (C₁ -C₇)alkoxymethyl,a (C₁ -C₇)acyloxymethyl, a (C₁ -C₇)alkylaminocarbonyloxymethyl, a --CH₂NR₁₃ R₁₄ group with R₁₃ and R₁₄ other than hydrogen, a --CH₂ NR₃ COR₄group with R₄ other than (C₁ -C₃)alkyl when R₃ is hydrogen, a --CH₂ NR₃COOR₈ group, a CH₂ NR₃ SO₂ R₉ group, a --CH₂ NR₃ CONR₁₀ R₁₂ group,

or T represents a methylene, or a --CONR₅ -- group with R₅ other thanhydrogen,

or -T-A- represents the --SO₂ -- group form a preferred group of thecompounds of the invention. Among the compounds of formula (III), thosein which:

either R₂ represents a (C₅ -C₇)alkoxy, a (C₅ -C₇)acyloxy, an --NR₃ COR₄group, with R₄ other than hydrogen or (C₁ -C₃)alkyl, an --NR₆ R₇ groupwith R₆ and R₇ other than H or (C₁ -C₄)alkyl or, when R₆ and R₇ togetherwith the nitrogen atom to which they are attached constitute aheterocycle, other than pyrrolidine, piperidine or morpholine, an --NR₃COOR₈ group, an --NR₃ SO₂ R₉ group, an --NR₃ CONR₁₀ R₁₂ group, a (C₁-C₇)acyl, a (C₅ -C₇)alkoxycarbonyl, a --CONR₁₀ R₁₂ group, a --CH₂ OHgroup, a (C₁ -C₇)alkoxymethyl, a (C₁ -C₇)acyloxymethyl, a (C₁-C₇)alkylaminocarbonyloxymethyl, a --CH₂ NR₁₃ R₁₄ group, a --CH₂ NR₃COR₄ group, an --NR₃ COOR₈ group, a --CH₂ NR₃ COOR₈ group, a --CH₂ NR₃SO₂ R₉ group, a --CH₂ NR₃ CONR₁₀ R₁₂ group,

or T represents a --CONR₅ -- group, a --COO-- group,

or A represents a vinylene,

or -T-A- represents the --SO₂ -- group form another preferred group ofthe compounds of the invention. Particularly preferred are the compoundsof formula (IV): ##STR5## in which: R'₃ represents a hydrogen or methyl;

R'₄ represents a (C₄ -C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls;

or R'₃ and R'₄ together represent a --(CH₂)_(n) -- group;

n is 3 or 4; as well as their salts.

The salts of compounds of formulae (II), (III) and (IV) according to thepresent invention comprise both those with organic or inorganic acidswhich permit suitable separation or crystallization of the compounds offormulae (II), (III) and (IV), such as picric acid or oxalic acid or anoptically active acid, for example a mandelic or camphosulfonic acid,and those which form pharmaceutically acceptable salts as describedabove for the compounds of formula (I).

1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-benzoylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(acetyl-N-methylamino)-4-phenylpiperidin-1-yl)-propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(pyrid-2-yl)carboxamido-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(isobutyryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-valerylamino-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(propionyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(butyryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(valeryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-(isovaleryl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

1-benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloyl-N-methylamino)-4-phenylpiperidin-1-yl)propyl!-piperidine,

in the form of racemates or of one of their (+) or (-) enantiomers,

and their salts are particularly preferred compounds according to thepresent invention.

The compounds according to the invention are obtained by known methods,in particular those which are described in Patent Applications EP 474561 and EP 512 901.

One of the processes which is suitable for producing the compounds offormula (I) is described below. According to this process

a) a compound of formula: ##STR6## in which R₁, R₁₁ have the definitionsgiven above for the compounds of formula (I) and E represents a hydroxylor optionally an O-protected group such as for example atetrahydropyran-2-yloxy, a benzoyloxy or a (C₁ -C₄)alkylcarbonyloxy or agroup: ##STR7## in which Ar is as defined above and R'₂ represents R₂ asdefined above for (I) or a precursor of R₂, it being understood thatwhen R'₂ is a hydroxyl or an amino group, these groups may be protected,is treated

either with a functional derivative of an acid of formula:

    HOCO--A--Z                                                 3

in which A and Z are as defined above for (I), when it is necessary toprepare a compound of formula (I) where T-- is --CO--,

or with a halogenated derivative of formula:

    Hal--CH.sub.2 --A--Z                                       4

in which Hal represents a halogen, preferably bromine or chlorine, whenit is necessary to prepare a compound of formula (I) where T is --CH₂--:

or with a chloroformate of formula:

    ClCOOAZ                                                    5

when it is necessary to prepare a compound of formula (I) where T is--COO--,

or with an isocyanate derivative of formula:

    O═C═N--AZ                                          6

when it is necessary to prepare a compound of formula (I) where T is--CONH--,

or with a carbamoyl chloride of formula: ##STR8## when it is necessaryto prepare a compound of formula (I) where T is --CONR₅ -- with R₅different from hydrogen,

or with a benzenesulfonyl chloride of formula

    ClSO.sub.2 --Z                                             7a

when it is necessary to prepare a compound of formula (I) in which--T--A-- is --SO₂ -- in order to obtain a compound of formula: ##STR9##b) the O-protecting group is optionally removed by the action of an acidor of a base,

c) the alcohol thus obtained of formula: ##STR10## is treated with acompound of the formula:

    W--SO.sub.2 --Cl                                           9a

in which W represents a methyl, phenyl, tolyl or trifluoromethyl group,

d) the sulphonate thus obtained of formula: ##STR11## is reacted with asecondary amine of formula: ##STR12## in which Ar and R'₂ are as definedabove, e) after optional deprotection of the hydroxyl or of the aminorepresented by R'₂ or possible conversion of R'₂ to R₂, the productobtained is optionally converted to one of its salts.

In step c) the compound 9a is advantageously methanesulfonyl chlorideand therefore, in the compound 10 of step d), W is advantageously amethyl group.

When, in the compound of formula 1, E represents a group: ##STR13## theprocess comprises only steps a) and e).

According to a variant of the process,

a1) the amine function of the compound of formula 1 is protected by aprotecting group in order to prepare a compound of formula: ##STR14## inwhich E, R₁, R₁₁ are as defined above and Pr represents anitrogen-protecting group, for example a tert-butoxycarbonyl (Boc), atrityl, a benzyl,

b1) the O-protecting group is optionally removed by the action of anacid or of a base,

c1) the alcohol thus obtained of formula: ##STR15## is treated with acompound of formula 9a described above, d1) the sulfonate of formula:##STR16## thus obtained is reacted with a secondary amine: ##STR17## togive the compound of formula: ##STR18## e1) the nitrogen is deprotectedin acidic medium, f1) the compound of formula: ##STR19## thus obtainedis treated with one of the compounds 3, 4, 5, 6, 7 or 7a describedabove,

g1) after optional deprotection of the hydroxyl or the amino representedby R'₂ or optional conversion of R'₂ to R₂, the product of formula (I)obtained is optionally converted to one of its salts.

In step c₁) the compound 9a is advantageously methanesulfonyl chlorideand therefore, in the compound 14 of step d₁), W is advantageously amethyl group.

The O-protecting groups optionally used to obtain a compound of formula(I) in which R₂ represents a hydroxyl are conventional O-protectinggroups well known to persons skilled in the art as defined above for E.

The N-protecting groups optionally used to obtain a compound of formula(I) in which R₂ represents an amino are conventional N-protecting groupswell known to persons skilled in the art such as for example the trityl,methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.

In particular, when an acetyl group is used as O-protecting group, thecompound of formula (I) obtained represents the final product in whichR₂ represents an acetoxy or when a tert-butoxycarbonyl group is used asN-protecting group, the compound of formula (I) obtained represents thefinal product in which R₂ represents a tert-butoxycarbonylamino.

Particularly advantageous operating conditions of the above steps arehereinafter given and illustrated by the Examples.

In stage a), as functional derivative of the acid 3, the acid itself isused, or alternatively one of the functional derivatives which normallyreact with amines, for example an anhydride, a mixed anhydride, the acidchloride, or an activated ester such as paranitrophenyl ester.

When the acid of formula 3 itself is used, the procedure is carried outin the presence of a coupling agent used in peptide chemistry such as1,3-dicyclohexyl-carbodiimide orbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphatein the presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethaneor N,N-dimethylformamide at a temperature of between 0° C. and roomtemperature.

When an acid chloride is used, the reaction is carried out in an inertsolvent such as dichloromethane or benzene, in the presence of a basesuch as triethylamine or N-methylmorpholine and at a temperature between-60° C. and room temperature.

When a halogenated derivative of formula 4 is used, the reaction iscarried out in an inert solvent such as tetrahydrofuran,N,N-dimethylformamide or dimethyl sulfoxide in the presence of a basesuch as potassium tert-butoxide, sodium hydride or lithiumdiisopropylamide and at a temperature between 0° C. and 80° C.

When a chloroformate of formula 5 is used, the reaction is carried outin an inert solvent such as dichloromethane, in the presence of a basesuch as triethylamine and at a temperature between 0° C. and roomtemperature.

When an isocyanate of formula 6 is used, the reaction is carried out inan inert solvent such as dichloromethane or benzene and at a temperaturebetween -70° C. and room temperature.

When a carbamoyl chloride of formula 7 is used, the reaction is carriedout in an inert solvent such as toluene or 1,2-dichloroethane, at atemperature between 0° C. and 110° C. and in the presence of a base suchas triethylamine.

When a benzenesulfonyl chloride of formula 7a is used, the reaction iscarried out in an inert solvent such as dichloromethane, in the presenceof a base such as triethylamine and at a temperature between -20° C. androom temperature.

The compound of formula 8 thus obtained is optionally deprotected atstage b) according to methods known to persons skilled in the art. Forexample, when E represents a tetrahydropyran-2-yloxy group, thedeprotection is carried out by acid hydrolysis using hydrochloric acidin a solvent such as ether, methanol, or the mixture of these solvents,or using pyridinium p-toluenesulfonate in a solvent such as methanol oralternatively, using an Amberlyst® resin in a solvent such as methanol.The reaction is carried out at a temperature between room temperatureand the reflux temperature of the solvent. When E represents abenzoyloxy group or a (C₁ -C₄)alkylcarbonyloxy group, the deprotectionis carried out by hydrolysis in alkaline medium using for example analkali metal hydroxide such as sodium hydroxide, potassium hydroxide orlithium hydroxide, in an inert solvent such as water, methanol, dioxaneor a mixture of these solvents, at a temperature between 0° C. and thereflux temperature of the solvent.

At stage c), the reaction of the alcohol of formula 9 with a sulfonylchloride of formula 9a is preferably carried out in the presence of abase such as triethylamine, pyridine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent such as dichloromethane, benzeneor toluene, at a temperature between -20° C. and the reflux temperatureof the solvent.

When a compound of formula 10 is reacted with a compound of formula 11(stage d), the reaction is preferably carried out in an inert solventsuch as N,N-dimethylformamide, acetonitrile, methylene chloride, tolueneor isopropanol and in the presence or in the absence of a base. When abase is used, it is chosen from organic bases such as triethylamine,N,N-diisopropylethylamine or N-methyl-morpholine or from alkali metalcarbonates or bicarbonates such as potassium carbonate, sodium carbonateor sodium bicarbonate. In the absence of a base, the reaction is carriedout using an excess of the compound of formula 11 and optionally in thepresence of an alkali metal iodide such as potassium iodide or sodiumiodide. The reaction is carried out at a temperature between roomtemperature and 100° C.

The products of formula (I) thus obtained are either isolated in theform of a free base or a salt, according to conventional techniques.

When the compound of formula (I) is obtained in the form of a free base,the salification is carried out by treating with the chosen acid in anorganic solvent. By treating the free base, dissolved for example in anether such as diethyl ether or in an alcohol such as propan-2-ol or inacetone, with a solution of the chosen acid in the same solvent, thecorresponding salt is obtained which is isolated according toconventional techniques.

Thus, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate,dihydrogen phosphate, methanesulfonate, oxalate, maleate, fumarate,naphthalene-2-sulfonate, benzenesulfonate are for example prepared.

At the end of the reaction, the compounds of formula (I) can be isolatedin the form of one of their salts, for example the hydrochloride or theoxalate; in this case, if necessary, the free base can be prepared byneutralizing the said salt with an inorganic or organic base, such assodium hydroxide or triethylamine or with an alkali metal carbonate orbicarbonate, such as sodium or potassium carbonate or bicarbonate.

The substituted piperidines of formula 11 are known or prepared by knownmethods.

The compounds of formula 11 are generally prepared in a form protectedon the piperidine nitrogen; they make it possible to obtain, by adeprotection step, the compounds of formula 11 themselves. For example,when Ar is a pyrid-2-yl, 2-bromopyridine is reacted withN-benzyl-4-piperidone in a solvent in the presence of buytllithium inorder to prepare N-benzyl-4-hydroxy-4-pyrid-2-ylpiperidine, and then bydeprotection in a basic medium 4-hydroxy-4-pyrid-2-ylpiperidine.

The compounds of formula 11 in which R'₂ represents a hydroxyl and whichcarry a protecting group on the piperidine nitrogen can be subjected toa Ritter reaction by the action of acetonitrile in order to prepare thecompounds of formula 11 in which R'₂ is an acetamido according to theprocedure described in Patent Application EP-474561. By hydrolysis inacidic medium, the compounds of formula 11 in which R'₂ is an amino arethen prepared. Optionally, it is possible to carry out the substitutionof the amino group by a group R₃ =(C₁ -C₄)alkyl. The compounds offormula 11 in which R'₂ represents an --NR₃ COR₄ -- group in which R₃represents a hydrogen or a (C₁ -C₄)alkyl and R₄ represents a hydrogen orrespectively a (C₁ -C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which is optionally substituted, are obtained by theaction of formic acid in acetic anhydride or respectively of theappropriate anhydride (R₄ CO)₂ O or of an appropriate acid chloride R₄COCl in the presence of a base such as triethylamine, on a compound offormula 11 in which R'₂ represents an --NHR₃ group.

In particular, a compound of formula 11 in which R'₂ represents an --NR₃COR₄ group in which R₄ represents an ethyl radical can be prepared byhydrogenation, in the presence of a catalyst such as palladium oncharcoal, of a compound of formula 11 in which R'₂ represents anacryloylamino or acryloyl-N-(C₁ -C₄)alkylamino group.

The compounds of formula 11 in which R'₂ is the --NR₃ COOR₈ group areprepared by the action of a chloroformate ClCOOR₈. The compounds offormula 11 in which R'₂ is the --NR₃ SO₂ R₉ group are prepared by theaction of a sulfonyl chloride ClSO₂ R₉. The compounds of formula 11 inwhich R'₂ is the --NR₃ CONR₁₀ R₁₂ group with R₁₀ =H are prepared by theaction of an isocyanate R₁₂ N═C═O. The compounds of formula 11 in whichR'₂ is the --NR₃ CONR₁₀ R₁₂ group are prepared by the action of acarbamoyl chloride R₁₂ R₁₀ NCOCl.

A compound of formula 11 in which R'₂ is an --NR₃ CONR₁₀ R₁₂ group canalso be obtained by reacting a compound HNR₁₀ R₁₂ with a compound offormula 11 in which R'₂ is an --NR₃ COOR₈ group with R₈ =phenyl.

It goes without saying that the reactions leading to the compounds offormula 11 where R'₂ is --NHR₃, --NR₃ COOR₈, --NR₃ SO₂ R₉ or --NR₃CONR₁₀ R₁₂ are directly transposable to the preparation of the compounds11 where R'₂ is --CH₂ NHR₃, --CH₂ NR₃ COOOR₈, --CH₂ NR₃ SO₂ R₉ or --CH₂NR₃ CONR₁₀ R₁₂.

A compound of formula 11 in which R'₂ is an --NR₆ R₇ group in which R₆and R₇ together with the nitrogen to which they are attached constitutea heterocycle, is prepared according to the method described inTetrahedron Letters, 1988, 29 (52), 6827.

A compound of formula 11 in which R'₂ is a hydroxymethyl is prepared byreducing a compound of formula 11 in which R'₂ is a methoxycarbonyl bythe action of a reducing agent such as lithium aluminum hydride. Thecompounds of formula 11 in which R'₂ is a (C₂ -C₇)acyloxymethyl areobtained by the action of a (C₂ -C₇) acid chloride on a compound offormula 11 in which R'₂ is a hydroxymethyl; the compound of formula 11in which R'₂ is a formyloxymethyl is obtained by the action of formicacid. The compounds of formula 11 in which R'₂ is a (C₁-C₇)alkylaminocarbonyloxymethyl are obtained by the action of acarbamoyl chloride (C₁ -C₇)alkylNHCOCl on a compound of formula 11 inwhich R'₂ is a hydroxymethyl.

A compound of formula 11 in which Ar and R'₂ together with the carbonatom to which they are attached constitute a group of formula: ##STR20##is prepared according to the method described in J. Heteroc. Chem.,1969, 6, 475.

The compounds of formula 11 in which R'₂ is a (C₂ -C₇)acyloxy areobtained by the action of a (C₂ -C₇) acid chloride on the compounds offormula 11 in which R'₂ represents a hydroxyl; the compounds of formula11 in which R'₂ is a formyloxy are obtained by the action of formicacid.

To prepare a compound of formula 11 in which R'₂ is R₄ CONR₃ --, with R₃and R₄ together representing a --(CH₂)₃ -- or --(CH₂)₄ -- group, theprocedure is carried out according to J. Med. Chem., 1985, 2, 46-50.

The conversion of a substituent R₂ =cyano to a substituent R₂=aminomethyl can be carried out by catalytic hydrogenation either on acompound of formula 11, or on a compound of formula (I). Compoundsaccording to the invention, variously substituted on the aminomethylnitrogen, are then prepared by appropriate reactions.

The above methods are well known and are illustrated by the Preparationsbelow, preceding the EXAMPLES. These preparations constitute adaptationsof the methods described in EP-A-0,428,434, EP-A-0,474,561,EP-A-0,512,901 or in the following publications.

J. Heterocyclic. Chem., 1986, 3, 73-75

J. Chem. Soc., 1950, 1469

J. Chem. Soc., 1945, 917

J. Pharmaceutical. Sci., 1972, 6, 1316-1317

J. Org. Chem. 1957, 2, 1484-1489.

Thus for example, to prepare a compound of formula 11 in which R'₂represents an --NR₆ R₇ group in which R₆ represents a hydrogen and R₇represents a (C₁ -C₇)alkyl, or respectively a (C₃ -C₇)cycloalkylmethylor a benzyl, a reduction can be carried out of a compound of formula 11in which R'₂ represents an --NR₃ COR₄ group in which R₃ representshydrogen and R₄ represents a hydrogen or a (C₁ -C₆)alkyl, orrespectively a (C₃ -C₇)cycloalkyl or a phenyl. The reaction is carriedout by means of a reducing agent such as lithium aluminum hydride in asolvent such as tetrahydrofuran at the reflux temperature of thesolvent.

By an identical reaction, the compounds of formula 11 in which R'₂represents an --NR₆ R₇ group in which R₆ represents a (C₁ -C₄)alkyl andR₇ represents a (C₁ -C₇)alkyl, or respectively a (C₃-C₇)cycloalkylmethyl or a benzyl, can be prepared from a compound offormula 11 in which R'₂ represents an --NR₃ COR₄ group in which R₃represents a (C₁ -C₄)alkyl and R₄ represents a hydrogen or a (C₁-C₆)alkyl, or respectively a (C₃ -C₇)-cycloalkyl or a phenyl. Likewise,the compounds of formula 11 in which R'₂ represents an --NR₆ R₇ group inwhich R₆ represents a (C₅ -C₇)alkyl can be prepared.

Likewise, the compounds of formula 11 in which R'₂ represents a --CH₂NR₁₃ R₁₄ group in which R₁₃ represents a hydrogen or a (C₁ -C₄)alkyl andR₁₄ represents a (C₁ -C₇)alkyl, a (C₃ -C₇)cycloalkylmethyl or a benzyl,can be prepared from a compound of formula 11 in which R'₂ represents a--CH₂ NR₃ COR₄ group in which R₃ represents a hydrogen or a (C₁-C₄)alkyl and R₄ represents a hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₇)-cycloalkyl or a phenyl. Likewise, the compounds of formula 11 inwhich R'₂ represents a --CH₂ NR₁₃ R₁₄ group in which R₁₃ represents a(C₅ -C₇)alkyl can be prepared.

The conversion of a substituent R₂ =hydroxyl or hydroxymethyl to asubstituent R₂ =(C₁ -C₇)acyloxy or (C₁ -C₇)acyloxymethyl can be carriedout either on a compound of formula 11 or on a compound of formula (I).

Optionally, the conversions of the R₂ group from R'₂ =hydroxyl or aminocan be carried out on a compound of formula 15.

The piperidine derivatives of formula: ##STR21## in which Ar is asdefined above for (I);

R'₂ represents an --NR₃ COR₄ group with R₃ and R₄ as defined above for(I), provided that when R₃ is hydrogen, R₄ is other than methyl;

Y represents hydrogen or a protecting group such as atert-butoxycarbonyl, a trityl or a benzyl; as well as their salts whereappropriate are new and constitute a subsequent aspect of the presentinvention.

Advantageous products amongst these compounds are those of formula (V)in which Ar is phenyl, R'₂ is an --NR₃ COR₄ group, R₃ being methyl andR₄ being (C₁ -C₇)alkyl, and Y is hydrogen or an N-protecting group, aswell as their possible salts.

Particularly preferred according to the invention are the compounds offormula (V), in which Ar is phenyl, R'₂ is an --NR₃ COR₄ group, R₃ andR₄ both being methyl, and Y is hydrogen or a protecting group, inparticular tert-butoxycarbonyl, trityl or benzyl, as well as theirpossible salts.

The compounds of formula 1 in which E represents a hydroxyl are preparedby known methods. The following SCHEME 1 summarizes one of these methodsfor the compounds of formula 1'. ##STR22##

Compounds 3, 4, 5, 6, 7, 7a are known or prepared by known methods.

These compounds can be used in labeled form, for example with tritium,or with radioactive iodine, in order to prepare compounds (I) accordingto the invention which are labeled.

In this case, the procedure is carried out starting with a compound 3,4, 5, 6, 7, 7a in which the radical Z is substituted by an iodine atom,then this iodine atom is exchanged with a tritium or a radioactiveiodine atom in order to prepare a labeled compound 3*, 4*, 5*, 6*, 7*and 7*a which makes it possible to prepare a labeled compound of formula(I*), more particularly a labeled compound of formula (IV*).

The alcohol (1') obtained according to scheme 1 is racemic. Theseparation of its optical isomers can be optionally carried out by knownmethods, for example by chromatography or recrystallization, then thecorresponding optically pure mesylate can be prepared and the compoundsaccording to the invention can thus be prepared in optically pure form.

The alcohol (1'), which constitutes the key intermediate in thesynthesis of the compounds of formula (IV), which are particularlypreferred as potent and selective antagonists of the human NK₃ receptor,is a new compound. The racemic form of this alcohol, the two (+) and (-)enantiomers and the salts of these compounds are therefore anotheraspect of the present invention, the isomer (+) and its acid additionsalts being particularly preferred.

According to another aspect, the subject of the present invention is theuse of a nonpeptide compound which is a specific antagonist of the humanNK₃ receptor having a very high affinity for said receptor, for thepreparation of medicinal products which are useful in the treatment ofany pathology in which neurokinin B is involved, in particular for thepreparation of medicinal products intended to combat psychiatricdiseases, diseases of psychosomatic origin, hypertension, pathologieslinked to NK₃ -dependent neuromodulation or neurotransmission disorders.

The invention relates in particular to the use of a compound of formula(I'): ##STR23## in which: Ar represents a pyrid-2-yl or a phenyl whichis unsubstituted or substituted by a halogen, a methyl or a (C₁-C₄)alkoxy;

R₁ represents a methyl group;

R₁₁ represents hydrogen;

or R₁ and R₁₁ together represent a --(CH₂)₃ -- group;

R₂ represents a hydroxyl; a (C₁ -C₇)alkoxy; a (C₁ -C₇)acyloxy; a cyano;an --NR₆ R₇ group; an --NR₃ COR₄ group; an --NR₃ COOR₈ group; an --NR₃SO₂ R₉ group; an --NR₃ CONR₁₀ R₁₂ group; a (C₁ -C₇)acyl group; a (C₁-C₇)alkoxycarbonyl; a --CONR₁₀ R₁₂ group; a --CH₂ OH group; a (C₁-C₇)alkoxymethyl; a (C₁ -C₇)acyloxymethyl; a (C₁-C₇)alkylaminocarbonyloxymethyl; a --CH₂ NR₁₃ R₁₄ group; a --CH₂ NR₃COR₄ group; a --CH₂ NR₃ COOR₈ group; a --CH₂ NR₃ SO₂ R₉ group; a --CH₂NR₃ CONR₁₀ R₁₂ group; or R₂ constitutes a double bond between the carbonatom to which it is attached and the adjacent carbon atom of thepiperidine ring;

or Ar and R₂, together with the carbon atom to which they are attached,constitute a group of formula: ##STR24## R₃ represents a hydrogen or a(C₁ -C₄)alkyl; R₄ represents a hydrogen, a (C₁ -C₇)alkyl, a phenyl, abenzyl, a pyridyl or a (C₃ -C₇)cycloalkyl which is unsubstituted orsubstituted by one or more methyls;

or R₃ and R₄ together represent a --(CH₂)_(n) -- group;

n is 3 or 4;

T represents a methylene, a carbonyl, a --COO-- group, a --CONR₅ --group;

A represents a direct bond, a methylene, an ethylene, a propylene, avinylene;

or --T--A-- represents the --SO₂ -- group

Z represents a phenyl which is unsubstituted or substituted one orseveral times by a halogen, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, a nitro;

R₅ represents a hydrogen or a (C₁ -C₄)alkyl;

R₆ and R₇ each represent independently a hydrogen or a (C₁ -C₇)alkyl; R₇can furthermore represent a (C₃ -C₇)cycloalkylmethyl, a benzyl or aphenyl; or R₆ and R₇, together with the nitrogen atom to which they areattached, constitute a heterocycle chosen from azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine or perhydroazepine;

R₈ represents a (C₁ -C₇)alkyl or a phenyl;

R₉ represents a (C₁ -C₇)alkyl; an amino which is free or substituted byone or two (C₁ -C₇)alkyls; a phenyl which is unsubstituted orsubstituted once or several times by a substituent chosen from: ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro, an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different;

R₁₀ and R₁₂ each represent independently a hydrogen or a (C₁ -C₇)alkyl;R₁₂ may furthermore represent a (C₃ -C₇)cycloalkyl, a (C₃-C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl; or R₁₀ and R₁₂, together with the nitrogen atom to which theyare attached, constitute a heterocycle chosen from azetidine,pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine;

R₁₃ and R₁₄ each represent independently a hydrogen or a (C₁ -C₇)alkyl;R₁₄ may furthermore represent a (C₃ -C₇)cycloalkylmethyl or a benzyl;

or of its pharmaceutically acceptable salts, for the preparation ofmedicinal products as defined above and advantageously for thepreparation of medicinal products which are useful for treatinghypertension.

The affinity of the compounds of formula (I') for the tachykininreceptors was evaluated in vitro by several biochemical assays usingradioligands:

1) The binding of ¹²⁵ I!BH-SP (substance P labeled with iodine 125 withthe aid of the Bolton-Hunter reagent) to the NK₁ receptors of ratcortex, of guinea pig ileum and of human lymphoblastic cells.

2) The binding of ¹²⁵ I!His-NK_(A) to the NK₂ receptors of rat duodenumor of guinea pig ileum.

3) The binding of ¹²⁵ I!His MePhe⁷ !NK_(B) to the NK₃ receptors of ratcerebral cortex, of guinea pig cerebral cortex and of gerbil cerebralcortex as well as to the cloned human NK₃ receptors expressed by CHOcells (Buell et al., FEBS Letters, 1992, 299, 90-95).

The assays were carried out according to X. Emonds-Alt et al. (Eur. J.Pharmacol., 1993, 250, 403-413).

The compounds according to the invention strongly inhibit the binding of¹²⁵ I!His MePhe⁷ !NK_(B) to the NK₃ receptors of guinea pig and gerbilcerebral cortex as well as to cloned human NK₃ receptors; the inhibitionconstant Ki is generally less than 5.10⁻⁹ M. For the same compounds, itwas observed that the inhibition constant (Ki) for the NK₃ receptors ofrat cerebral cortex is greater than 10⁻⁷ M and that the inhibitionconstant (Ki) for the NK₂ receptor of rat duodenum and the NK₁ receptorsof rat cortex is generally greater than or equal to 10⁻⁷ M.

By way of comparison, the inhibition constants for the various receptorsfor compound A were measured according to the procedures describedabove. The antagonism of the eledoisin binding described in ApplicationEP 512901 corresponds to the inhibition constant of the rat NK₃receptor:

    Ki=10.sup.-7 M

For the human NK₃ receptor, the inhibition constant of compound A isKi=1.10⁻⁹ M.

For the rat duodenum NK₂ receptor, the inhibition constant of compound Ais Ki=1.10⁻¹⁰ M.

Thus, compound A is not selective for the human NK₃ receptor contrary towhat is observed for the compounds of formula (I) according to thepresent invention.

The N-methyl-N- 2-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenylpiperidin-1-yl)pentyl!benzamidehydrochloride described in Example 22 of Application EP 474561 belongsto the family of compounds (I') according to the present invention; itsinhibition constants show the high specificity and the high affinity ofthis compound for the human NK₃ receptor:

human NK₃ receptor, Ki=5.10⁻⁹ M

rat duodenum NK₂ receptor, Ki=5.10⁻⁷ M

rat cortex NK₁ receptor, Ki=5.10⁻⁷ M.

The compounds according to the present invention were also evaluated invivo on two animal models.

In gerbils, a rotating behavior is induced by intrastriataladministration of an NK₃ receptor-specific agonist: senktide; it wasobserved that a unilateral application of senktide in the gerbilstriatum leads to strong contralateral rotations which are inhibited bythe compounds according to the invention when administered eitherintraperitoneally or orally.

This result shows that the compounds according to the invention crossthe hematomeningeal barrier and that they are capable of blocking, inthe central nervous system, the action specific to the NK₃ receptors.They can thus be used for the treatment of any NK_(B) -dependent centralpathology, such as psychiatric diseases, or of any pathology mediated,at the central level, by the NK₃ receptor, such as psychosomaticdiseases.

In guinea pigs, an intravenous or intracerebroventricular injection ofsenktide induces a hypertension which is suppressed by the oral orintravenous administration of the compounds according to the invention.

This result shows that the compounds according to the invention act atthe cardiovascular level and that they are capable of blocking theaction specific to the NK₃ receptors at this level, especiallyhypertension (Nakayama et al., Brain Res. 1992, 595 339-342, Takano andKamiya, Asia Pacific, J. Pharmacol., 1991, 6, 341-346, Saigo et al.,Neuroscience Letters, 1993, 15, 187-190).

In these tests, the compounds according to the invention are active atdoses ranging from 0.1 mg to 3 mg per kg orally, intravenously orintraperitoneally.

The compounds which are useful for preparing medicinal productsaccording to the invention are generally administered as dosage units.Preferred dosage units are preferably formulated in pharmaceuticalcompositions in which the active ingredient is mixed with apharmaceutical excipient.

According to another of its aspects, the present invention relates topharmaceutical compositions containing, as active ingredient, a compoundof formula (I), advantageously of formula (II) or (III), preferably offormula (IV) having a very high affinity for the human NK₃ receptor,characterized by an inhibition constant Ki of less than 5.10⁻⁹ M inligand binding studies.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used at daily doses of 0.01 to 100 mg per kilo of body weight ofthe mammal to be treated, preferably at daily doses of 0.1 to 50 mg/kg.In humans, the dose may range preferably from 0.5 to 4000 mg per day,more particularly from 2.5 to 1000 mg according to the age of thesubject to be treated or the type of treatment: prophylactic orcurative.

The diseases for the treatment of which the compounds and theirpharmaceutically acceptable salts can be used are for example diseasesassociated with a dysfunction of the dopaminergic systems such asschizophrenia, Parkinson's disease, diseases associated with adysfunction of the noradrenergic systems such as anxiety, vigilancedisorders as well as epileptic diseases of any form and in particularGrand Mal, dementia, neurodegenerative diseases, and peripheral diseasesin which the participation of the central nervous system and/or theperipheral nervous system occurs via neurokinin B acting as centralneurotransmitter or neuromodulator, such as pain, migraine, acute orchronic inflammation, cardiovascular disorders, in particularhypertension, cardiac insufficiency, and rhythm disorders, respiratorydisorders (asthma, rhinitis, cough, bronchitis, allergies,hypersensitivity), disorders of the gastrointestinal system such asesophageal ulcer, colitis, stress-related disorders, irritable bowelsyndrome (IBS), inflammatory bowel diseases (IBD), acidic secretion,disorders of the urinary system (incontinence, neurogenic bladder),diseases of the immune system (rheumatoid arthritis), and more generallyany neurokinin B-dependent pathology.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhaled, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active ingredients canbe administered in unit forms for administration, mixed withconventional pharmaceutical carriers, to animals and to humans. Theappropriate unit forms for administration comprise the oral forms suchas tablets, gelatin capsules, powders, granules and oral solutions orsuspensions, the forms for sublingual and buccal administration, theforms for subcutaneous, intramuscular, intravenous, intranasal orintraocular administration and the forms for rectal administration.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle such as silica,gelatin, starch, lactose, magnesium stearate, talc, gum arabic and thelike. The tablets can be coated with sucrose, with various polymers orwith other appropriate materials or alternatively they can be treated sothat they have a prolonged or delayed activity and that they release apredetermined quantity of active ingredient continuously.

A gelatin capsule preparation is obtained by mixing the activeingredient with a diluent such as a glycol or a glycerol ester andincorporating the mixture obtained into soft or hard gelatin capsules.

A preparation in the form of syrup or elixir may contain the activeingredient together with a sweetener which is preferably calory free,methylparaben and propylparaben as antiseptic, as well as a tasteenhancing agent and an appropriate coloring.

Water-dispersible powders or granules may contain the active ingredientmixed with dispersing agents or wetting agents, or suspending agents,such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

For rectal administration, suppositories are used which are preparedwith binders melting at the rectal temperature, for example cocoa butteror polyethylene glycols.

For a parenteral, intranasal or intraocular administration, aqueoussuspensions, isotonic saline solutions or injectable solutionscontaining pharmacologically compatible dispersing agents and/or wettingagents, for example propylene glycol or butylene glycol, are used.

For administration by inhalation, an aerosol is used containing, inaddition, for example sorbitan trioleate or oleic acid as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propelling gas; a system containingthe active ingredient, alone or combined with an excipient, in the formof a powder can also be used.

The active ingredient may also be present in the form of a complex witha cyclodextrin, for example α-, β-, γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin.

The active ingredient may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

In each dosage unit, the active ingredient of formula (I) is present inquantities adapted to the expected daily doses. In general, each dosageunit is suitably adjusted according to the dosage and the type ofadministration intended, for example tablets, gelatin capsules and thelike, sachets, ampoules, syrups and the like, drops, so that such adosage unit contains from 0.5 to 1000 mg of active ingredient,preferably from 2.5 to 250 mg to be administered once to four times perday.

The abovementioned compositions may also contain other active productswhich are useful for the desired therapy, such as for examplebronchodilators, anti-coughs or antihistaminics.

By virtue of their very high affinity for the human NK₃ receptor andtheir high selectivity, it will be possible to use the compoundsaccording to the invention in radiolabeled form as laboratory reagents.

For example they make it possible to carry out the characterization,identification and localization of the human NK₃ receptor in tissuesections, or of the NK₃ receptor in the whole animal by autoradiography.

The compounds according to the invention also make it possible to carryout the sorting or screening of molecules according to their affinityfor the human NK₃ receptor. In this case, the procedure is carried outby a reaction for displacing the radiolabeled ligand, which is thesubject of the present invention, from its human NK₃ receptor.

In the examples which follow, the following abbreviations are used:

RT: room temperature

m.p.: melting point

TEA: triethylamine

Pd/C: 10% palladium on charcoal

DCM: dichloromethane

THF: tetrahydrofuran

DBU: 1,8-diazabicyclo 5.4.0!undec-7-ene

DMAP: 4-dimethylaminopyridine

AcOEt: ethyl acetate

MeOH: methanol

HPLC: high-performance liquid chromatography

Me: methyl

iPr: isopropyl

Bu: n-butyl

HCl: hydrochloric acid

(Boc)₂ O: di-tert-butyl dicarbonate

Boc=tert-butoxycarbonyl

BOP: benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate

NaCl: sodium chloride

MgSO₄ : magnesium sulfate

Na₂ SO₄ : sodium sulfate

LiAlH₄ : lithium aluminum hydride

NaOH: sodium hydroxide

NH₄ Cl: ammonium chloride

ether: diethyl ether

isoether: diisopropyl ether

Et: ethyl

C₆ H5: phenyl

K₂ CO₃ : potassium carbonate

hydrochloric ether: saturated solution of HCl in ether

silica H: silica gel 60 H marketed by Merck (DARMSTADT)

NMR: nuclear magnetic resonance

s: singlet

bs: broad singlet

d: doublet

t: triplet

m: unresolved complex

mt: multiplet

st: split triplet

ss: split singlet

PREPARATIONS PREPARATION 1.1 4-Phenyl-4-pivaloylaminopiperidine.

A) 1-Benzyl-4-hydroxy-4-phenylpiperidine

This compound is prepared by the action of phenyllithium on1-benzylpiperidin-4-one.

B) 4-Acetamido-1-benzyl-4-phenylpiperidine.

This compound is obtained according to the Ritter reaction by theaddition of acetonitrile onto the compound prepared in stage A.

C) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride.

The compound prepared in stage B is hydrolyzed by refluxing for 3 hoursin 6N HCl. After evaporation to dryness, the residue is dissolved inmethanol, crystallized by addition of acetone, filtered and dried togive the expected compound.

D) 1-Benzyl-4-phenyl-4-pivaloylaminopiperidine.

70 g of the compound prepared in the preceding stage are dissolved in150 ml of dioxane, 85 ml of TEA are added followed by 45 g of pivaloylchloride. After stirring for 2 hours at 60° C., the mixture isevaporated, taken up in DCM, washed with dilute sodium hydroxide, with asolution of NaCl and then dried over MgSO₄ and evaporated. The residueis chromatographed on silica, eluting with DCM. 43 g of the expectedproduct are obtained in the form of an oil.

E) 4-Phenyl-4-pivaloylaminopiperidine.

13 g of the compound obtained in the preceding stage are dissolved in 20ml of 95% ethanol; 1.5 g of Pd/C are added and the mixture ishydrogenated for 24 hours at room temperature, at atmospheric pressure,filtered, evaporated so as to obtain an oil which crystallizes giving 8g of expected product.

PREPARATION 1.2 4-Phenyl-4-(pivaloyl-N-methylamino)piperidine.

A) 1-Benzyl-4-(N-tert-butoxycarbonylamino)-4-phenylpiperidine.

A solution of 12 g of (Boc)₂ O in 50 ml of dioxane is added dropwise toa solution of 14.5 g of 4-amino-1-benzyl-4-phenylpiperidinedihydrochloride obtained in stage C of Preparation 1.1, 12 ml of TEA in100 ml of dioxane, and the mixture is heated for 18 hours at 50° C. Thereaction mixture is concentrated under vacuum, the residue extractedwith AcOEt, washed with a buffer solution pH=2, with a 1N solution ofNaOH, dried over MgSO₄ and the solvent evaporated under vacuum. 13 g ofthe expected product are obtained after crystallization from theether/heptane mixture.

B) 4-(N-tert-butoxycarbonylamino)-4-phenylpiperidine.

A mixture of 13 g of the compound obtained in the preceding stage, 1.5 gof 10% palladium on charcoal in 300 ml of 95% EtOH is hydrogenated for72 hours at RT and at atmospheric pressure. The catalyst is filtered onCelite® and the filtrate evaporated under vacuum. 9.7 g of the expectedproduct are obtained.

C) 4(N-tert-butoxycarbonylamino)-4-phenyl-1-tritylpiperidine.

13.25 g of the compound obtained in the preceding stage and 5 g of TEAare dissolved in 150 ml of DCM at 0° C., under nitrogen. 13.4 g oftrityl chloride are added dropwise and the mixture is kept stirring for1 hour. The reaction mixture is evaporated, taken up in ether, washedwith water, with a buffer solution at pH 2, a solution of NaCl, and thendried over MgSO₄ and evaporated. 23 g of the expected product areobtained in the form of an oil.

D) 4(N-Methylamino)-4-phenyl-1-tritylpiperidine.

A suspension of 5 g of LiAlH4 in 100 ml of THF is heated to 60° C.,under nitrogen, and a solution of 23 g of the compound obtained in thepreceding stage in 100 ml of THF is added dropwise. After refluxing for2 hours, the reaction mixture is hydrolyzed with 25 ml of water,filtered, evaporated. 17 g of the expected product are obtained, whichproduct crystallizes from hot methanol, m.p.=125° C.

E) 4-(Pivaloyl-N-methylamino)-4-phenyl-1-tritylpiperidine.

2.6 g of the compound obtained in the preceding stage are dissolved in15 ml of pyridine, 500 mg of DMAP and 4 ml of pivaloyl chloride areadded. The mixture is allowed to react for 72 hours at 70° C. undernitrogen and then evaporated, dissolved in AcOEt, washed with water, abuffer solution at pH=2, a 5% solution of sodium hydroxide, a solutionof NaCl, and then dried over MgSO₄. The residue is chromatographed onsilica, eluting with a pentane/AcOEt mixture. The expected product (1.5g) is obtained in the form of an oil.

F) 4-Phenyl-4-(Pivaloyl-N-methylamino)piperidine.

1.5 g of the product obtained in the preceding stage are dissolved in amixture of 20 ml of formic acid and 20 ml of water. After stirring for 1hour, the reaction mixture is filtered, the filtrate neutralized by theaddition at cold temperature of a 40% solution of NaOH and thenextracted 3 times with 50 ml of DCM; the resulting material is driedover MgSO₄ and evaporated. 700 mg of the expected product are obtainedin the form of a pasty product, m.p.=50-55° C.

PREPARATION 1.3 4-(Acetyl-N-methylamino)-4-phenylpiperidine.

A) 4-(Acetyl-N-methylamino)-4-phenyl-1-tritylpiperidine.

A solution of 2.8 g of the compound obtained in stage D of thePreparation 1.2 in 20 ml of DCM is cooled to 0° C., under nitrogen, and1.5 ml of TEA are added, followed by 0.55 g of acetyl chloride. Themixture is kept stirring for 2 hours and the reaction lo mixture isconcentrated under vacuum. The residue is taken up in AcOEt, washed witha buffer solution pH=2, with a 5% solution of NaOH, with a saturatedsolution of NaCl, dried over MgSO₄ and the solvent evaporated undervacuum. 3 g of the expected product is are obtained.

B) 4-(Acetyl-N-methylamino)-4-phenylpiperidine

A solution of 3 g of the compound obtained in the preceding stage, 30 mlof formic acid in 15 ml of water is heated at 60° C. for 1 hour. 50 mlof water are added to the reaction mixture ; it is filtered, thefiltrate washed with ether, the aqueous phase alkalinized to pH>10 byaddition of a concentrated solution of NaOH, extracted with DCM, driedover MgSO₄ and the solvent evaporated under vacuum. 1 g of the expectedproduct is obtained in the form of an oil.

PREPARATION 1.4 4- (Acetyl-N-methylamino)methyl!-4-phenylpiperidinep-toluenesulfonate.

A) 4(Aminomethyl)-1-benzyl-4-phenylpiperidine.

A suspension of 2.8 g of lithium aluminum hydride in 50 ml of THF iscooled to 0° C. and a solution of 20 g of1-benzyl-4-cyano-4-phenylpiperidine in 50 ml of THF is added dropwise.The mixture is kept stirring for 1 hour at RT and then heated at 40° C.for 1 hour. The reaction mixture is cooled on an ice bath, and 3 ml ofwater, 3 ml of a 4N solution of NaOH and 12 ml of water are addedsuccessively. The inorganic salts are filtered and the filtrateevaporated under vacuum. The residue is chromatographed on silica H,eluting with the gradient of the DCM/MeOH mixture from (100/3; v/v) to(100/10; v/v). 11 g of the expected product are obtained.

B) 1-Benzyl-4- (N-formylamino)methyl!-4-phenylpiperidine.

25 ml of acetic anhydride are added, at RT and dropwise, to a mixture of11 g of the compound obtained in the preceding stage in 76 ml of formicacid, then the mixture is kept stirring for 5 hours. The reactionmixture is concentrated under vacuum, the residue taken up in water,alkalinized to pH=14 by addition of concentrated NaOH, extracted withether, washed with water, dried over Na₂ SO₄ and the solvent evaporatedis under vacuum. 12 g of the expected product are obtained.

C) 1-Benzyl-4- (N-methylamino)methyl!-4-phenylpiperidine.

A suspension of 3.9 g of lithium aluminum hydride in 50 ml of THF isheated to 40° C., a solution of 12 g of the compound obtained in thepreceding stage in 50 ml of THF is added dropwise and the mixturerefluxed for 3 hours. After cooling on an ice bath, 4 ml of water, 4 mlof a 4N solution of NaOH and 12 ml of water are added successively. Theinorganic salts are filtered and the filtrate concentrated under vacuum.The residue is extracted with ether, dried over Na2SO₄ and the solventevaporated under vacuum. 10 g of the expected product are obtained.

D) 4- (Acetyl-N-methylamino)methyl!-1-benzyl-4-phenylpiperidine.

0.863 g of acetyl chloride is added to a solution of 3.3 g of thecompound obtained in the preceding stage, 1.4 g of triethylamine in 50ml of DCM, and the mixture is kept stirring for 2 hours at RT. Thereaction mixture is concentrated under vacuum, the residue taken up inwater, extracted with ether, washed with water, dried over Na₂ SO₄ andthe solvent evaporated. The residue is chromatographed on silica H,eluting with the DCM/MeOH mixture (100/3; v/v). 2.4 g of the expectedproduct are obtained.

E) 4- (acetyl-N-methylamino)methyl!-4-phenylpiperidinep-toluenesulfonate.

A mixture of 2.3 g of the compound obtained in the preceding stage, 1.2g of p-toluenesulfonic acid monohydrate, 0.23 g of 10% palladium oncharcoal and 100 ml of MeOH is hydrogenated at RT and at atmosphericpressure. The catalyst is filtered and the filtrate evaporated undervacuum. 2.7 g of the expected product are obtained.

PREPARATION 1.5 4- (N'-Ethyl-N-methylureido)methyl!-4-phenylpiperidine.

A) 1-Benzyl-4- (N'-ethyl-N-methylureido)methyl!-4-phenylpiperidine.

A solution of 0.71 g of ethyl isocyanate in 10 ml of DCM is added at RTto a solution of 2.7 g of the compound obtained in stage C of thePREPARATION 1.4 in 50 ml of DCM and the mixture is kept stirring for 1hour. The reaction mixture is concentrated under vacuum and the residuechromatographed on silica H, eluting with the DCM/MeOH mixture (100/2.5;v/v). 1.7 g of the expected product are obtained.

B) 4- (N'-Ethyl-N-methylureido)methyl!-4-phenylpiperidine.

A mixture of 1.7 g of the compound obtained in the preceding stage, 0.2g of 10% palladium on charcoal and 50 ml of MeOH is hydrogenated at 40°C. and at atmospheric pressure. The catalyst is filtered and thefiltrate evaporated under vacuum. 1.23 g of the expected product areobtained.

PREPARATION 1.6 4-(N',N'-Diethyl-N-methylureido)methyl!-4-phenylpiperidinep-toluenesulfonate.

A) 1-Benzyl-4- (N',N'-diethyl-N-methylureido)methyl!-4-phenylpiperidine.

1.92 g of N,N-diethylcarbamoyl chloride are added at RT to a solution of4 g of the compound obtained in stage C of the PREPARATION 1.4, 1.55 gof triethylamine in 30 ml of 1,2-dichloroethane and the mixture isrefluxed for 2 hours. The reaction mixture is concentrated under vacuum,the residue extracted with ether, washed with water, dried over MgSO₄and the solvent evaporated under vacuum. The residue is chromatographedon silica H, eluting with the DCM/MeOH mixture (100/2; v/v). 2.5 g ofthe expected product are obtained.

B) 4- (N',N'-Diethyl-N-methylureido)methyl!-4-phenylpiperidinep-toluenesulfonate.

A mixture of 2.4 g of the compound obtained in the preceding stage, 1 gof p-toluenesulfonic acid monohydrate, 0.24 g of 10% palladium oncharcoal and 50 ml of MeOH is hydrogenated at 30° C. and at atmosphericpressure. The catalyst is filtered and the filtrate is evaporated undervacuum. 2.8 g of the expected product are obtained.

PREPARATION 1.7 4-Phenyl-4-(piperid-1-yl)piperidine dihydrochloride,dehydrate.

A) 1-Benzyl-4-cyano-4-(piperid-1-yl)piperidine.

12.16 g of piperidine hydrochloride and 18.9 g of 1-benzylpiperid-4-oneare dissolved in 50 ml of an MeOH/H₂ O mixture (50/50; v/v). 5.3 g ofNaCN dissolved in 20 ml of water are added dropwise. After stirring for48 hours, the precipitate formed is filtered, rinsed with water anddried to give 27 g of the expected product.

B) 1-Benzyl-4-phenyl-4-(piperid-1-yl)piperidine.

A solution of phenylmagnesium bromide is prepared from 1.5 g ofmagnesium, 12 g of phenyl bromide in 50 ml of ether. After stirring for1 hour, a solution of 10 g of the compound obtained in the precedingstage in 100 ml of ether is added dropwise at RT and the mixture is keptstirring for 30 minutes. The reaction mixture is poured over 300 ml of asaturated solution of ammonium chloride, washed with water afterdecanting, extracted with a 2N solution of HCl, the acidic aqueous phasewashed with DCM, the aqueous phase alkalinized by addition ofconcentrated NaOH, extracted with DCM, dried over MgSO₄ and the solventevaporated under vacuum. The oil obtained is chromatographed on silica,eluting with the DCM/MeOH/NH₄ OH mixture (50/50/1; v/v/v). 4.2 g of theexpected product are obtained after crystallization from isoether.

C) 4-Phenyl-4-(piperid-1-yl)piperidine dihydrochloride, dihydrate.

A solution of 1.6 g of CNBr in 20 ml of chloroform is added dropwise toa solution of 4 g of the compound obtained in the preceding stage in 25ml is of DCM and the mixture is refluxed for 1 hour. The reactionmixture is concentrated under vacuum, the residue taken up in 50 ml of a6N solution of HCl and refluxed for 4 hours. Then the mixture is keptstirring overnight at RT, animal charcoal is added, and the mixture isfiltered, the filtrate alkalinized by addition of 40% NaOH, extractedtwice with ether, dried over MgSO₄ and evaporated under vacuum. Theproduct obtained is taken up in DCM, acidified by addition ofhydrochloric ether and evaporated under vacuum. 3 g of the expectedproduct are obtained.

PREPARATION 1.8 4-(Formylamino)-4-phenylpiperidine hydrochloride.

A) 1-Benzyl-4-(formylamino)-4-phenylpiperidine hydrochloride.

4.5 ml of acetic anhydride are added dropwise to a solution of 2 g ofthe compound obtained in stage C of the PREPARATION 1.1, 0.9 g of sodiumformate in 14 ml of formic acid and the mixture is kept stirring for 48hours at RT. The reaction mixture is 35 concentrated under vacuum, theresidue taken up in water, alkalinized by addition of concentrated NaOH,extracted with DCM, dried over MgSO₄ and the solvent evaporated undervacuum. The product obtained is taken up in DCM, acidified to pH=1 byaddition of hydrochloric ether and evaporated under vacuum. 1.7 g of theexpected product are obtained after crystallization from acetone,m.p.=225° C. (dec).

B) 4-(Formylamino)-4-phenylpiperidine hydrochloride.

A mixture of 1.7 g of the compound obtained in the preceding stage, 0.2g of 10% palladium on charcoal and 50 ml of 95% EtOH is hydrogenated atRT and at atmospheric pressure. The catalyst is filtered and thefiltrate is evaporated under vacuum. 1.1 g of the expected product areobtained after crystallization from acetone, m.p.=217° C.

PREPARATION 1.9 4-(Formyl-N-ethylamino)-4-phenylpiperidinep-toluenesulfonate.

A) 1-Benzyl-4-(N-ethylamino)-4-phenylpiperidine.

A solution of 5 g of 4-acetamido-1-benzyl-4-phenylpiperidine in 50 ml ofTHF is added to a suspension of 1.5 g of lithium aluminum hydride in 20ml of THF and the mixture is refluxed for 3 hours. After cooling, asolution of 1 ml of concentrated NaOH in 8 ml of water is added, theinorganic salts are filtered and the filtrate is evaporated undervacuum. The oil obtained is dissolved in 50 ml of THF, this solution isadded to a suspension of 1.5 ml of lithium aluminum hydride in 20 ml ofTHF and the mixture is refluxed for 1 hour. The reaction mixture ishydrolyzed by addition of a solution of 0.5 ml of concentrated NaOH in 6ml of water, the inorganic salts filtered and the filtrate evaporatedunder vacuum. 4.8 g of the expected product are obtained, which productis used as it is in the next stage.

B) 1-Benzyl-4-(formyl-N-ethylamino)-4-phenylpiperidinep-toluenesulfonate.

13 ml of acetic anhydride are added dropwise to a solution of 4.8 g ofthe compound obtained in the preceding stage in 40 ml of formic acid andthe mixture is heated at 40°0 C. for 24 hours. 30 ml of formic acid areadded followed by 25 ml of acetic anhydride and the heating is continuedat 40° C. for 24 hours. 30 ml of formic acid are again added followed by25 ml of acetic anhydride and the heating is continued at 40° C. for 24hours. The reaction mixture is concentrated under vacuum, the residue istaken up in water, alkalinized by addition of concentrated NaOH,extracted with DCM, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is chromatographed on silica, eluting with DCM andthen with the DCM/MeOH mixture (97/3; v/v). The product obtained isdissolved in 50 ml of acetone, 2.8 g of p-toluenesulfonic acidmonohydrate are added and left to crystallize. 6.3 g of the expectedproduct are obtained, m.p.=199° C.

C) 4-(Formyl-N-ethylamino)-4-phenylpiperidine p-toluene sulfonate.

A mixture of 6.3 g of the compound obtained in the preceding stage, 0.7g of 10% palladium on charcoal and 100 ml of 95% EtOH is hydrogenated atRT and at atmospheric pressure. The catalyst is filtered and thefiltrate is evaporated under vacuum. 4.78 g of the expected product areobtained after crystallization from the acetone/ether mixture, m.p.=151°C.

PREPARATION 1.104-(Cyclopropylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A) 1-Benzyl-4-(N-methylamino)-4-phenylpiperidine.

A solution of 38.8 g of the compound obtained in stage A of thePREPARATION 1.8 (in the form of a free base, m.p.=140° C.) in 400 ml ofTHF is added dropwise to a suspension of 12.5 g of lithium aluminumhydride in 100 ml of THF and the mixture is refluxed for 3 hours. Thereaction mixture is hydrolyzed by addition of a solution of 5 ml ofconcentrated NaOH in 45 ml of water, the inorganic salts filtered andthe filtrate concentrated under vacuum. 38 g of the expected product areobtained, which product is used as it is in the next stage.

B) 1-Benzyl-4-(cyclopropylcarbonyl-N-methylamino)-4-phenylpiperidine.

A solution of 1.5 g of the compound obtained in the preceding stage, 1.5ml of triethylamine in 20 ml of DCM, is cooled to 0° C., and 0.58 ml ofcyclopropanecarbonyl chloride is added dropwise and the mixture is keptstirring for 2 hours while the temperature is allowed to rise to RT. Thereaction mixture is washed twice with water, with a 1N solution of NaOH,dried over MgSO₄ and the solvent evaporated under vacuum. 1.8 g of theexpected product are obtained.

C) 4-(Cyclopropylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A mixture of 1.8 g of the compound obtained in is the preceding stage,0.85 g of para-toluenesulfonic acid monohydrate, 0.35 g of 10% palladiumon charcoal and 100 ml of EtOH is hydrogenated at RT and at atmosphericpressure. The catalyst is filtered on Celite® and the filtrate isevaporated under vacuum. 1.5 g of the expected product are obtainedafter crystallization from the acetone/AcOEt mixture.

PREPARATION 1.11 4-(Cyclopropylcarbonylamino)-4-phenylpiperidinehydrochloride.

A) 1-Benzyl-4-(cyclopropylcarbonylamino)-4-phenylpiperidine.

A solution of 1 g of the compound obtained in stage C of the PREPARATION1.1, 1.7 ml of triethylamine in 30 ml of DCM is cooled to -20° C., 0.22ml of cyclopropanecarbonyl chloride is added dropwise and the mixture iskept stirring while allowing the temperature to rise to RT. The reactionmixture is extracted with DCM, washed twice with water, with a 0.5Nsolution of NaOH, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is taken up in AcOEt, the crystals formed spun,washed with AcOEt and then with ether. 0.77 g of the expected product isobtained.

B) 4-(Cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride.

A mixture of 0.77 g of the compound obtained in the preceding stage,0.14 g of 10% palladium on charcoal and 40 ml of EtOH is hydrogenated at35° C. and at atmospheric pressure. The catalyst is filtered and thefiltrate evaporated under vacuum. The residue is taken up in DCM,acidified to pH=1 by addition of hydrochloric ether and evaporated undervacuum. 0.6 g of the expected product is obtained.

PREPARATION 1.12 4-(Cyclobutylcarbonylamino)-4-phenylpiperidinehydrochloride.

A) 1-Benzyl-4-(cyclobutylcarbonylamino)-4-phenylpiperidine.

A solution of 1.5 g of the compound obtained in stage C of thePREPARATION 1.1, 2.1 ml of triethylamine in 30 ml of DCM is cooled to 0°C., 0.45 ml of cyclobutanecarbonyl chloride is added dropwise and themixture is kept stirring while allowing the temperature to rise to RT.The reaction mixture is extracted with DCM, washed twice with water,with a 0.5N solution of NaOH, dried over MgSO₄ and the solventevaporated under vacuum. 1.1 g of the expected product are obtainedafter crystallization from AcOEt and then recrystallization from ether.

B) 4-(Cyclobutylcarbonylamino)-4-phenylpiperidine hydrochloride.

A mixture of 1.1 g of the compound obtained in the preceding stage, 0.18g of 10% palladium on charcoal and 60 ml of EtOH is hydrogenated at 35°C. and at atmospheric pressure. The catalyst is filtered on Celite® andthe filtrate is evaporated under vacuum. The residue is taken up in DCM,acidified by addition of hydrochloric ether and evaporated under vacuum.0.92 g of the expected product is obtained.

PREPARATION 1.13 4-(Cyclohexylcarbonylamino)-4-phenylpiperidinehydrochloride.

A) 1-Benzyl-4-(cyclohexylcarbonylamino)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageA of the PREPARATION 1.12 from 1.5 g of the compound obtained in stage Cof the PREPARATION 1.1 and 0.75 ml of cyclohexanecarbonyl chloride. 1.3g of the expected product are obtained.

B) 4-(Cyclohexylcarbonylamino)-4-phenylpiperidine hydrochloride.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.12. 0.9 g of the expected product is obtained.

PREPARATION 1.14 4-Methoxycarbonyl-4-phenylpiperidinep-toluenesulfonate.

1 g of para-toluenesulfonic acid monohydrate is added to a solution of10 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml ofMeOH and the mixture is refluxed for 3 days. The reaction mixture isconcentrated under vacuum, the residue taken up in acetone and ether isadded until precipitation occurs. After spinning the precipitate formed,9.34 g of the expected product are obtained.

PREPARATION 1.15 4-(N-methylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine.

30 ml of water, 32.9 g of K₂ CO₃ are added to a mixture of 30 g of4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of dioxane,then the mixture is heated to 60° C. and 18.21 g of di-tert-butyldicarbonate are added slowly. The reaction mixture is then heated for 2hours at 60° C. and then refluxed for 30 minutes. The reaction mixtureis concentrated under vacuum, the residue taken up in DCM, washed withbuffer pH=2, acidified to pH=4 by addition of 2N HCl, extracted withDCM, washed with buffer pH=2, with water, with a saturated solution ofNaCl, dried over MgSO₄ and evaporated under vacuum. 23.7 g of theexpected product are obtained.

B) 1-tert-Butoxycarbonyl-4-(N-methylcarbamoyl)-4-phenylpiperidine.

1.98 g of triethylamine are added to a solution of 1.5 g of the compoundobtained in the preceding stage in 5 ml of DCM and 5 ml of DMF, followedby 0.49 g of methylamine hydrochloride. The mixture is cooled on an icebath, 2.39 g of BOP are added and the mixture is kept stirring for 24hours while allowing the temperature to rise to RT. The reaction mixtureis concentrated under vacuum, the residue extracted with ether, washedwith water, with a buffer solution pH=2, with water, with a 10% solutionof NaOH, with water, with a saturated solution of NaCl, dried over MgSO₄and evaporated under vacuum. 1.4 g of the expected product are obtained.

C) 4-(N-Methylcarbamoyl)-4-phenylpiperidine.

4 ml of concentrated HCl are added to a solution of 1.4 g of thecompound obtained in the preceding stage in 30 ml of MeOH and themixture is kept stirring for 1 hour at RT. The reaction mixture isconcentrated under vacuum, the residue extracted with DCM, washed withwater, twice with a 10% solution of NaOH, dried over MgSO₄ and thesolvent evaporated under vacuum. 0.6 g of the expected product isobtained.

PREPARATION 1.16 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(N-n-butylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1.0 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.24 g of n-butylamine. 1.3 g of theexpected product are obtained, which product is used as it is in thenext stage.

B) 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine

This compound is prepared according to the procedure described in stageC of the PREPARATION 1.15. 0.4 g of the expected product is obtained.

PREPARATION 1.17 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidinetrifluoroacetate.

A) 1-tert-Butoxycarbonyl-4-(N,N-diethylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1.5 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.8 g of diethylamine hydrochloride. 1.7 gof the expected product are obtained.

B) 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidine trifluoroacetate.

1.7 g of the compound obtained in the preceding stage are dissolved in20 ml of trifluoroacetic acid and the mixture is stirred at RT for 30minutes. The reaction mixture is concentrated under vacuum, the residuetaken up in ether and evaporated under vacuum. 2.8 g of the expectedproduct are obtained in the form of an oil.

PREPARATION 1.18 4-(Pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.23 g of pyrrolidine. 1.0 g of the expectedproduct is obtained.

B) 4-(Pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine.

3 ml of concentrated HCl are added to a solution of 1.0 g of thecompound obtained in the preceding stage in 25 ml of MeOH and themixture is stirred for 1 hour at 35-40° C. The reaction mixture isconcentrated under vacuum, the residue taken up in MeOH and the solventevaporated under vacuum. The residue is extracted with ether, washedtwice with a 10% solution of NaOH, with water, with a saturated solutionof NaCl, dried over MgSO₄ and the solvent evaporated under vacuum. 0.43g of the expected product is obtained.

PREPARATION 1.19 4-(N-Methoxy-N-methylcarbamoyl)-4-phenylpiperidine.

A)1-tert-Butoxycarbonyl-4-(N-methoxy-N-methylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1.5 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.71 g of O-methyl-N-methylhydroxylaminehydrochloride. 1.71 g of the expected product are obtained.

B) 4-(N-Methoxy-N-methylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageC of the PREPARATION 1.15 from 1.7 g of the compound obtained in thepreceding stage. 1.1 g of the expected product are obtained.

PREPARATION 1.20 4-(Methylsulfonamido)-4-phenylpiperidine hydrochloride.

A) 1-Benzyl-4-(methylsulfonamido)-4-phenylpiperidine p-toluenesulfonate.

A mixture of 5 g of the compound obtained in stage C of the PREPARATION1.1, 10 ml of triethylamine in 100 ml of DCM is cooled to 0° C., under anitrogen atmosphere, 2.68 g of mesyl chloride are added dropwise and themixture is kept stirring for 30 minutes. The reaction mixture isconcentrated under vacuum, the residue extracted with AcOEt, washedthree times with water, with a 10% solution of NaOH, with a saturatedsolution of NaCl, dried over MgSO₄ and the solvent evaporated undervacuum. The oil obtained is dissolved in 50 ml of acetone, 2.8 g ofp-toluenesulfonic acid monohydrate are added and, after stirring, themixture is evaporated under vacuum. 6.8 g of the expected product areobtained.

B) 4-(Methylsulfonamido)-4-phenylpiperidine hydrochloride.

A 40% solution of NaOH is added to a solution of 6.8 g of the compoundobtained in the preceding stage in water; the mixture is extracted withDCM, the organic phase is dried over MgSO₄ and the solvent is evaporatedunder vacuum. 2.3 g of 1-chloroethyl chloroformate, 1 ml of1,2,2,6,6-pentamethylpiperidine are added to the residue obtained (3.69g) and the mixture is kept stirring overnight. The reaction mixture isevaporated under vacuum, the residue is dissolved in MeOH and themixture is heated at 60° C. for 1 hour. The solvent is evaporated undervacuum, the residue is taken up in acetone and the crystals formed arespun. 3 g of the expected product are obtained.

PREPARATION 1.21 4-(Methanesulfonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A) 1-Benzyl-4-(methanesulfonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

1.6 ml of triethylamine are added to a solution of 2 g of the compoundobtained in stage A of the PREPARATION 1.10 in 30 ml of DCM followed by0.9 ml of mesyl chloride and then the mixture is kept stirring for 30minutes at RT. The reaction mixture is washed twice with water, with a5% solution of NaOH, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is taken up in ether, an insoluble matter isfiltered and the filtrate is evaporated under vacuum. The residue isdissolved in acetone, 1.4 g of p-toluene-sulfonic acid monohydrate areadded followed by ether until crystallization occurs. After spinning,2.3 g of the expected product are obtained, m.p.=175° C.

B) 4-(Methanesulfonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A mixture of 2.3 g of the compound obtained in the preceding stage, 0.25g of 10% palladium on charcoal in 40 ml of EtOH is hydrogenated at RTand at atmospheric pressure. The catalyst is filtered and the filtrateis evaporated under vacuum. 1.7 g of the expected product are obtainedin the form of a foam.

PREPARATION 1.22 4-(Cyclopropylmethylamino)-4-phenylpiperidinedi-p-toluenesulfonate.

A) 4-(Cyclopropylcarbonylamino)-4-phenyl-1-tritylpiperidine.

A mixture of 0.565 g of 4-(cyclopropylcarbonylamino)-4-phenylpiperidinehydrochloride in 50 ml of DCM is cooled to +5° C., 0.565 g of tritylchloride is added followed by 0.7 ml of triethylamine and the mixture iskept stirring while allowing the temperature to rise to RT. The reactionmixture is washed with water, the organic phase dried over MgSO₄ and thesolvent evaporated under vacuum. 1 g of the expected product is obtainedafter crystallization from ether.

B) 4-(Cyclopropylmethylamino)-4-phenyl-1-tritylpiperidine.

0.9 g of the compound obtained in the preceding stage is added to asuspension of 0.5 g of lithium aluminum hydride in 50 ml of THF and themixture is refluxed for 30 minutes. The reaction mixture is hydrolyzedby addition of 0.4 ml of a solution of concentrated NaOH in 3 ml ofwater, the inorganic salts are filtered and the filtrate is evaporatedunder vacuum. The product obtained is added to a suspension of 0.7 g oflithium aluminum hydride in 50 ml of THF and the mixture is refluxed for1 hour. The reaction mixture is hydrolyzed by addition of 0.5 ml of aconcentrated solution of NaOH in 4 ml of water, the inorganic saltsfiltered and the filtrate evaporated under vacuum. 0.5 g of the expectedproduct is obtained after crystallization from the DCM/isoether mixture.

C) 4-(Cyclopropylmethylamino)-4-phenylpiperidine di-p-toluenesulfonate.

A mixture of 0.5 g of the compound obtained in the preceding stage, 7.5ml of formic acid and 7.5 ml of water is heated at 50° C. for 1 hour.The reaction mixture is filtered, the filtrate alkalinized by additionof a 40% solution of NaOH, extracted with DCM, dried over MgSO₄ and thesolvent evaporated under vacuum. The product obtained is dissolved inDCM, 0.9 g of p-toluenesulfonic acid monohydrate is added and themixture is refluxed. After cooling, the crystals formed are spun. 0.35 gof the expected product is obtained after recrystallization from theacetone/ether mixture.

PREPARATION 1.23 4-Hydroxymethyl-4-phenylpiperidine.

A suspension of 1.16 g of lithium aluminum hydride in 50 ml of THF iscooled to -20° C., 4 g of the compound obtained in the PREPARATION 1.14are added and the mixture is kept stirring overnight while allowing thetemperature to rise to RT. The reaction mixture is hydrolyzed byaddition of 1.2 ml of water, followed by 2.5 ml of a 10% solution ofNaOH and 2.5 ml of water. The mixture is diluted with ether, theinorganic salts are filtered and the filtrate is evaporated undervacuum. 1.8 g of the expected product are obtained.

PREPARATION 1.24 4-Spiro(3-phthalide)piperidine hydrochloride.

A) 1-Benzyl-4-spiro(3-phthalide)piperidine.

A solution of 10 g of N-methylbenzamide in 100 ml of THF is cooled to-70° C. and 100 ml of a 1.6M solution of n-butyllithium in hexane areadded under nitrogen. The mixture is kept stirring while allowing thetemperature to rise to 0° C., then cooled to -70° C. and 7 g of1-benzylpiperid-4-one are added dropwise. The mixture is kept stirringfor 30 minutes, the reaction mixture is poured over 1 liter of ice coldwater, extracted twice with 500 ml of ether, the organic phase driedover MgSO₄ and the solvent evaporated under vacuum. The residue ischromatographed on silica, eluting with the DCM/MeOH mixture (99/1;v/v). 2.7 g of the expected product are obtained.

B) 4-Spiro(3-phthalide)piperidine hydrochloride.

A solution of 1 g of the compound obtained in the preceding stage, in 20ml of DCM, is cooled to 0° C., 0.51 g of 1-chloroethyl chloroformate isadded under a nitrogen atmosphere and the mixture is kept stirring for 2hours at RT. The reaction mixture is concentrated under vacuum, theresidue taken up in 10 ml of MeOH and heated at 50° C. for 35 minutes.The mixture is concentrated under vacuum. 0.66 g of the expected productis obtained after crystallization from acetone, m.p.=280° C. (dec).

PREPARATION 1.25 4-Hydroxy-4-(pyrid-2-yl)piperidine dihydrochloride.

A) 1-Benzyl-4-hydroxy-4-(pyrid-2-yl)piperidine hydrochloride.

25 g of 2-bromopyridine are dissolved in 100 ml of THF at -70° C., undernitrogen, and a 1.6M solution of n-butyllithium in hexane is addeddropwise followed by a solution of 30 g of 1-benzyl-piperid-4-one in 25ml of THF. The temperature is allowed to rise to RT, and, after onehour, the solvents are partially evaporated, the residue is poured overa saturated solution of NH₄ Cl, extracted with ether, washed with water,dried over MgSO₄ and evaporated. An oil is obtained which is dissolvedin 200 ml of DCM and gaseous HCl is bubbled so as to form thehydrochloride. The expected product (21 g) crystallizes from amethanol/ether mixture, m.p.=185° C.

B) 4-Hydroxy-4-(pyrid-2-yl)piperidine dihydrochloride.

17.7 g of the compound obtained in the preceding stage are dissolved ina minimum of water, 40% sodium hydroxide is added, the mixture isextracted with DCM, dried over MgSO₄ and evaporated. 15 g of the productof stage A are thereby obtained in the form of a free amine. The productis dissolved in 150 ml of ethanol, 2.5 g of 10% Pd/C and 17 g ofammonium formate are added. After stirring for 2 hours at RT and thenrefluxing for 2 hours, the mixture is evaporated, the residue is takenup in chloroform, washed with a 5% solution of sodium hydroxide, asaturated solution of NaCl, dried over MgSO₄ and evaporated. The residueis dissolved in methanol and forms the dihydrochloride (10 g) byaddition of a 4N solution of HCl in ether, m.p.=230° C.

PREPARATION 1.26 4-Hydroxy-4-(2-methoxyphenyl)piperidine.

A) 1-Benzyl-4-hydroxy-4-(2-methoxyphenyl)piperidine.

A solution of 15 g of 2-bromoanisole in 50 ml of THF is cooled to -70°C., under nitrogen, a 1.6M solution of n-butyllithium in THF is addeddropwise and the mixture is kept stirring for 1 hour. The mixture iscooled to -70° C. and a solution of 15.2 g of 1-benzylpiperid-4-one in50 ml of THF is added dropwise. The mixture is kept stirring whileallowing the temperature to rise to RT and after 1 hour, the reactionmixture is concentrated under vacuum. The residue is taken up in AcOEt,the organic phase washed with water, with a saturated solution of NaCl,dried over MgSO₄ and the solvent evaporated under vacuum. 14 g of theexpected product are obtained after crystallization from theAcOEt/ether/heptane mixture.

B) 4-Hydroxy-4-(2-methoxyphenyl)piperidine.

A mixture of 5 g of the compound obtained in the preceding stage, 1 g of5% palladium on charcoal, 5 g of ammonium formate in 100 ml of MeOH iskept stirring for 2 hours. The reaction mixture is filtered and thefiltrate evaporated under vacuum. The residue is taken up in DCM, theorganic phase washed with a 40% NaOH solution, dried over MgSO₄ and thesolvent evaporated under vacuum. 2.2 g of the expected product areobtained, m.p.=200° C.

PREPARATION 1.27 4-(Ethylaminocarbonyloxymethyl)-4-phenylpiperidinehydrochloride.

A) 1-tert-Butoxycarbonyl-4-(hydroxymethyl)-4-phenylpiperidine. 26.05 gof di-tert-butyldicarbonate are added to a solution of 22.8 g of thecompound obtained in the PREPARATION 1.23 in 250 ml of1,2-dimethoxyethane and the mixture is refluxed for 2 hours. Thereaction mixture is concentrated under vacuum, the residue taken up inDCM, the organic phase washed with a buffer solution pH=2, with asaturated NaCl solution, dried over MgSO₄ and the solvent evaporatedunder vacuum. 17.86 g of the expected product are obtained aftercrystallization from ether, m.p.=134° C.

B)1-tert-Butoxycarbonyl-4-(ethylaminocarbonyloxymethyl)-4-phenylpiperidine.

A mixture of 2.91 g of the compound obtained in the preceding stage, 2.4g of ethyl isocyanate, 2 drops of triethylamine in 30 ml of toluene iskept stirring overnight at RT. Then the reaction mixture is heated at100° C. for 24 hours and concentrated under vacuum. The residue is takenup in ether, the organic phase washed with a buffer solution pH=2, witha saturated solution of NaCl, dried over MgSO₄ and the solventevaporated under vacuum. 3.85 g of the expected product are obtained inthe form of an oil.

C) 4-(Ethylaminocarbonyloxymethyl)-4-phenylpiperidine hydrochloride.

10 ml of concentrated HCl are added to a solution of 3.85 g of thecompound obtained in the preceding stage in 50 ml of MeOH and themixture is heated at 60° C. for 2 hours. The mixture is concentratedunder vacuum, the residue taken up in acetone and the solvent evaporatedunder vacuum. 2.6 g of the expected product are obtained aftercrystallization from the AcOEt/ether mixture, m.p.=240-242° C.

PREPARATION 1.28 4-Phenyl-4-(propionyl-N-methylamino)piperidinep-toluenesulfonate.

A) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidine.

A solution of 1.5 g of the compound obtained in stage A of thePREPARATION 1.10, 1.5 ml of triethylamine in 40 ml of DCM is cooled to0° C., 0.5 ml of acryloyl chloride is added dropwise and the mixture iskept stirring while allowing the temperature to rise to RT. The reactionmixture is poured into water, extracted with DCM, the organic phasewashed with water, with a 2N solution of NaOH, dried over MgSO₄ and thesolvent evaporated under vacuum. 1.3 g of the expected product areobtained after crystallization from the ether/pentane mixture.

B) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidinep-toluenesulfonate.

0.59 g of p-toluenesulfonic acid monohydrate is added to a solution of1.15 g of the compound obtained in the preceding stage in 10 ml of DCMand the mixture is allowed to crystallize. 1.65 g of the expectedproduct are obtained.

C) 4-Phenyl-4-(propionyl-N-methylamino)piperidine p-toluenesulfonate.

A mixture of 1.64 g of the compound obtained in the preceding stage, 0.2g of 10% palladium on charcoal in 100 ml of EtOH is hydrogenated at RTand at atmospheric pressure. The catalyst is filtered on Celite® and thesolvent evaporated under vacuum. 1.3 g of the expected product areobtained.

PREPARATION 1.29 4-(Cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A) 1-Benzyl-4-(cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

0.78 ml of cyclohexanecarbonyl chloride is added at RT and dropwise to asolution of 1.5 g of the compound obtained in stage A of the PREPARATION1.10, 1.5 ml of triethylamine in 15 ml of DCM and the mixture is keptstirring for 2 hours. The reaction mixture is washed twice with water,with a 2N solution of NaOH, the organic phase dried over MgSO₄ and thesolvent evaporated under vacuum. The residue is dissolved in DCM, 0.97 gof p-toluenesulfonic acid monohydrate is added and the mixture isconcentrated under vacuum. 3.3 g of the expected product are obtainedafter crystallization from the AcOEt/ether mixture.

B) 4-(Cyclohexylcarbonyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate.

A mixture of 3.3 g of the compound obtained in the preceding stage, 0.35g of 10% palladium on charcoal in 100 ml of EtOH is hydrogenated at RTand at atmospheric pressure. The catalyst is filtered and the filtrateevaporated under vacuum. The residue is taken up in acetone and thesolvent evaporated under vacuum. 2.2 g of the expected product areobtained after crystallization from the AcOEt/ether mixture, m.p.=160°C.

PREPARATION 1.30 4-Carbamoyl-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-carbamoyl-4-phenylpiperidine.

A solution of 1.5 g of the compound obtained in stage A of thePREPARATION 1.15, 0.99 g of triethylamine, 2.39 g of BOP in 10 ml of DCMis cooled to -20° C. and then ammonia gas is bubbled through thesolution. The temperature is allowed to rise to RT and the mixture iskept stirring for 2 hours. The reaction mixture is concentrated undervacuum, the residue extracted with ether, the organic phase washed withwater, with a buffer solution pH=2, with water, with a 10% solution ofNaOH, with water, with a saturated solution of NaCl, dried over MgSO₄and the solvent evaporated under vacuum. 1.32 g of the expected productare obtained.

B) 4-Carbamoyl-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageC of the PREPARATION 1.15 from 1.32 g of the compound obtained in thepreceding stage. 0.41 g of the expected product is obtained.

PREPARATION 1.31 4-(N,N-Dimethylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(N,N-dimethylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1.5 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.6 g of dimethylamine hydrochloride. 1.6 gof the expected product are obtained.

B) 4-(N,N-Dimethylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageC of the PREPARATION 1.15 from 1.6 g of the compound obtained in thepreceding stage. 1.1 g of the expected product are obtained.

PREPARATION 1.32 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine.

A) 1-tert-Butoxycarbonyl-4-(N-isopropylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageB of the PREPARATION 1.15 from 1.5 g of the compound obtained in stage Aof the PREPARATION 1.15 and 0.29 g of isopropylamine. 1.61 g of theexpected product are obtained.

B) 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine.

This compound is prepared according to the procedure described in stageC of the PREPARATION 1.15 from 1.61 g of the compound obtained in thepreceding stage. 1.1 g of the expected product are obtained.

PREPARATION 2.12-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)-pentylamine.

A) 2-(3,4-Dichlorphenyl)-5-(tetrahydropyran-2-yloxy)-pentanenitrile.

15 g of sodium hydride at 60% in oil are suspended in 200 ml ofanhydrous THF. A solution of 69.5 g of 3,4-dichlorophenylacetonitrile in500 ml of THF is added dropwise over 30 minutes and then the reactionmixture is stirred at RT for 1 hour. The mixture is cooled to -20° C.and a solution of 85 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in100 ml of THF is added. The mixture is allowed to return to RT and after2 hours it is poured over a solution of 50 g of ammonium chloride in 3liters of water. The mixture is extracted with ether, washed with asaturated solution of sodium chloride, decanted, dried over MgSO₄ andconcentrated. The residue is chromatographed on silica gel, eluting witha mixture of toluene and an AcOEt gradient (3 to 5%). The pure productfractions are concentrated to give 77 g of expected product in the formof an oil.

B) 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)-pentylamine.

77 g of nitrile obtained in the preceding stage are dissolved in 500 mlof absolute ethanol. 200 ml of concentrated ammonia are added followedby Raney® nickel (10% of the quantity of starting nitrile). The mixtureis then hydrogenated under a hydrogen atmosphere at RT and atmosphericpressure, 10.5 of hydrogen are absorbed and the catalyst separated byfiltration on Celite®. The filtrate is concentrated under vacuum and theresidue is taken up in a solution of NaCl. After extraction with etherand drying using MgSO₄, 75 g of the expected product are obtained in theform of an oil.

PREPARATION 2.2 N-Methyl-2-(3,4-dichlorophenyl)-5-hydroxypentylaminehydrochloride.

A) Ethyl N-2-(3,4-dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentyl!carbamate.

20 g of the compound obtained in the PREPARATION 2.1 are dissolved in200 ml of DCM and 9.3 ml of TEA are added. The mixture is cooled to -50°C. and a solution of 6.3 ml of ethyl chloroformate is added dropwise.After 15 minutes, the mixture is washed with water and then with diluteHCl . The mixture is dried over MgSO₄ and concentrated to dryness togive 24 g of oil.

B)N-Methyl-2-(3,4-dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentylamine.

A solution of 24 g of carbamate obtained in the preceding stage in 100ml of anhydrous THF is added to 5 g of LiAlH₄ suspended in 150 ml ofTHF. The mixture is refluxed for 2 hours. The reaction mixture ishydrolyzed with 20 ml of water and 5 ml of concentrated sodiumhydroxide, the inorganic material is filtered and to filtrate isconcentrated to dryness. 20.1 g of the expected product are obtained inthe form of an oil.

C) N-Methyl-2-(3,4-dichlorophenyl)-5-hydroxypentylamine hydrochloride.

20 g of the compound obtained in the preceding stage are dissolved in200 ml of absolute ethanol. 8 ml of concentrated HCl are added and themixture is stirred at RT for 2.5 hours. The reaction mixture isconcentrated to dryness, ethanol and toluene are added and the mixtureagain concentrated to dryness. The residue is gradually crystallizedfrom acetone by adding ether. It is filtered and dried. 15.8 g of theexpected product are obtained, m.p.=124° C.

PREPARATION 2.3 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidinehydrochloride.

A) Methyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate.

37.2 g of 3,4-dichlorophenylacetonitrile and 34.43 g of methyl acrylateare dissolved in 20 ml of dioxane in a three-necked round-bottomedflask; 1 ml of DBU is added, the mixture is heated for 2 hours at 60°C., evaporated, diluted with 400 ml of ethyl acetate and then washedwith dilute HCl, a solution of NaCl, dried over MgSO₄ and evaporated.The expected product is crystallized from 100 ml of ethyl acetate, and100 ml of ether with 100 ml of heptane. 47 g of the product areobtained.

B) Methyl 3- 5-(3,4-dichlorophenyl)-2-oxopiperid-5-yl!propionate.

40 g of the compound prepared in stage A are dissolved in 500 ml of2-methoxyethanol, 2 g of Raney® nickel are added and the mixture ishydrogenated at 40° C. at atmospheric pressure for 3 days. The mixtureis filtered, evaporated and the expected product is obtained in the formof an oil (39 g).

C) 3- 5-(3,4-Dichlorophenyl)-2-oxopiperid-5-yl!propanoic acid.

17 g of the compound prepared in the preceding stage are dissolved in250 ml of methanol, 2.8 g of potassium hydroxide and 10 ml of water areadded and the mixture is refluxed for 2 hours. The reaction mixture isevaporated to dryness, the oil obtained taken up in 200 ml of water andextracted with 100 ml of ethyl acetate. The aqueous phase is acidifiedwith a 30% solution of HCl and then the precipitate formed is filteredand dried. It is recrystallized from hot methanol and 18.3 g of theexpected compound are obtained.

D) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride.

5 g of the compound obtained in the preceding stage are dissolved in 20ml of THF, 75 ml of borane (concentration 1M in THF) are added and themixture is refluxed for 24 hours, under nitrogen. 25 ml of methanol, 50ml of 4N HCl are added and the mixture is kept stirring for 30 minutesand then 40% sodium hydroxide is added up to a pH greater than 10. Thereaction mixture is extracted 3 times with 150 ml of DCM, the organicphase dried over MgSO₄ and evaporated. The residue is dissolved in DCMwith a 4N solution of HCl in ether. After evaporation, a foam isobtained and the expected product (4.5 g) crystallizes from theAcOEt/ether mixture.

EXAMPLE 1 N-Methyl-N-2-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenylpiperid-1-yl)pentyl!benzamidehydrochloride.

A) N-2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentyl!benzamide.

15 g of amine obtained in the PREPARATION 2.1 are dissolved in 200 ml ofDCM. The solution is cooled to 0° C., 7 ml of TEA are added followed by5.3 ml of benzoyl chloride. The reaction mixture is then stirred at RTfor 30 minutes and then concentrated to dryness. The residue is taken upin ether, washed with water and then with a buffer solution pH=2 as wellas a solution of Na₂ CO₃. After drying and concentration, 19.5 g of theexpected product are obtained in the form of an oil.

B) N-Methyl-N- 2-(3,4-dichlorophenyl)-5-tetrahydropyran-2-yloxypentyl!benzamide.

A mixture of 19.5 g of the compound prepared in the preceding stage and3.1 g of sodium hydride at 60% in oil, in 200 ml of anhydrous THF isstirred at RT. The mixture is heated at 40° C. for 1 hour and 7.7 ml ofmethyl iodide are added. After stirring for 1 hour at 40° C., themixture is concentrated to dryness, the residue is taken up in water,extracted with ether, washed with a buffer solution pH=2 and then withan Na₂ CO₃ solution. It is dried over MgSO₄ and evaporated. 21 g of theexpected product are obtained in the form of an oil.

C) N-Methyl-N- 2-(3,4-dichlorophenyl)-5-hydroxypentyl!-benzamide.

21 g of the compound obtained in the preceding stage are dissolved in170 ml of methanol in the presence of 5 ml of Amberlyst® 15 resin andthe mixture is refluxed for 2 hours. The mixture is filtered on Celite®,the filtrate is concentrated under vacuum and the residuechromatographed on silica gel, eluent: DCM then DCM/AcOEt up to pureAcOEt. 13.5 g of the expected product are obtained in the form of anoil.

D) N-Methyl-N- 2-(3,4-dichlorophenyl)-5-mesyloxypentyl!-benzamide.

13.5 g of alcohol obtained in the preceding stage and 5.7 ml of TEA in150 ml of DCM are stirred at 0° C. 3.2 ml of mesyl chloride are thenadded dropwise. After 15 minutes, the mixture is concentrated todryness, taken up in ether and washed twice with water. The mixture isdried over MgSO₄ and the solvent evaporated. 16.2 g of the expectedproduct are obtained in the form of an oil.

E) N-methyl-N-2-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenylpiperid-1-yl)pentyl!benzamide.

A mixture of 1 g of mesylate obtained in the preceding stage, 800 mg of4-hydroxy-4-phenylpiperidine and 3 ml of DMF is heated at 70° C. for 3hours. After cooling, the mixture is poured over water and extractedwith AcOEt and then washed with a solution of NaCl. The mixture is driedover MgSO₄ and the solvent evaporated. The product is chromatographed onsilica, eluent: DCM with a MeOH gradient (2 to 5%). 400 mg of theexpected product are obtained.

The hydrochloride of this compound is described in Application EP 474561 in Example 22, m.p.=148° C.

EXAMPLE 2 N-Methyl-N-2-(3,4-dichlorophenyl)-5-(4-propionyloxy-4-phenylpiperid-1-yl)pentyl!benzamidehydrochloride.

400 mg of the compound obtained in Example 1 and 0.19 ml of TEA in 10 mlof DCM are stirred at RT. 0.13 ml of propionyl chloride is addeddropwise and the mixture is washed with water then with a bicarbonatesolution. The mixture is dried over MgSO₄ and the solvent evaporated.The product is chromatographed on silica gel, eluent: DCM with an MeOHgradient (from 1% to 2%). The hydrochloride is formed after dissolutionin DCM and addition of hydrochloric ether. The solvent is evaporated andthe hydrochloride is concreted from ether. 320 mg of the expectedproduct are obtained, m.p.=112° C.

EXAMPLE 3 N-Methyl-N-2-(3,4-dichlorophenyl)-5-(4-acetamido-4-phenylpiperid-1-yl)pentyl!phenylacetamidehydrochloride.

A) N-Boc-N-methyl-2-(3,4-dichlorophenyl)-5-hydroxypentylamine.

15.8 g of amino alcohol obtained in the PREPARATION 2.2 are dissolved in150 ml of dioxane. 15 ml of water are added followed by 10 ml of TEA and12.7 g of Boc₂ O. The mixture is heated at 60° C. for 1 hour. Thereaction mixture is then concentrated to dryness, taken up in ether,washed with water and then with a dilute solution of HCl. The mixture isdried over MgSO₄ and the solvent evaporated. 19.2 g of the expectedproduct are obtained in the form of an oil.

B) N-Boc-N-methyl-2-(3,4-dichlorophenyl)-5-mesyloxypentylamine. 19.2 gof alcohol prepared in the preceding stage and 9.8 ml of TEA are stirredin 200 ml of DCM at 0° C. 5.4 ml of mesyl chloride are then addeddropwise. After 15 minutes, the mixture is concentrated to dryness,taken up in ether, washed with water then with Na₂ CO₃. The mixture isdried over MgSO₄ and the solvent evaporated. 23.5 g of the expectedproduct are obtained in the form of an oil.

C)N-Boc-N-methyl-5-(4-acetamido-4-phenylpiperid-1-yl)-2-(3,4-dichlorophenyl)pentylamine.

A mixture of 10 g of mesylate obtained in the preceding stage, 14 g of4-acetamido-4-phenylpiperidine and 20 ml of DMF is heated at 70° C. for2 hours. After cooling, the mixture is poured over ice and extractedwith AcOEt, washing with a dilute solution of sodium hydroxide and asolution of NaCl. The mixture is dried over MgSO₄ and the solventevaporated. The product is chromatographed on silica, eluting with DCMcontaining MeOH (gradient up to 10%). 11.6 g of the expected product areobtained.

D)N-Methyl-5-(4-acetamido-4-phenylpiperid-1-yl)-2-(3,4-dichlorophenyl)pentylaminedihydrochloride.

11 g of the compound prepared in the preceding stage are dissolved in 50ml of methanol. 20 ml of concentrated HCl are added and the mixture isstirred for 1 hour. The mixture is concentrated to dryness, taken up ina minimum of methanol and poured over ether. The mixture is filtered anddried to give 11.5 g of the expected product, m.p.=170° C.

E) N-Methyl-N-2-(3,4-dichlorophenyl)-5-(4-acetamido-4-phenylpiperid-1-yl)pentyl!phenylacetamidohydrochloride

280 mg of phenylacetic acid are added to 1 g of the dihydrochlorideobtained in the preceding stage dissolved in 20 ml of DCM, followed by0.92 ml of TEA and 1 g of BOP. After stirring for 15 minutes at RT, themixture is concentrated under vacuum, the residue taken up in AcOEt andwashed successively with water, with a dilute solution of sodiumhydroxide, with a solution of NaCl. The organic phase is dried overMgSO₄, filtered and concentrated under vacuum. The residue ischromatographed on silica gel, eluent: DCM with an MeOH gradient (3% to6%). The hydrochloride is formed after dissolution in DCM and additionof hydrochloric ether. The solvent is evaporated and the hydrochlorideis concreted from ether. 480 mg of the expected product are obtained,m.p.=137° C.

Other compounds according to the invention belonging to the family (II)have also been prepared and are described in TABLE 1 below.

                  TABLE 1                                                         ______________________________________                                                                       (II)                                           1 #STR25##                                                                    Example N°.                    m.p.                                    N°SR                                                                           R.sub.2    --T--A--Z--        ° C.                             ______________________________________                                        4       --NHCOCH.sub.3                                                                           --CO(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                             119                                     5       --NHCOCH.sub.3                                                                           --COOC.sub.6 H.sub.5                                                                             138                                     6       --NHCOCH.sub.3                                                                           --COOCH.sub.2 C.sub.6 H.sub.5                                                                    126                                     7       --NHCOCH.sub.3                                                                           2 #STR26##         139                                     8       --NHCOCH.sub.3                                                                           3 #STR27##         133                                     9       --NHCOCH.sub.3                                                                           --COCH═CH--C.sub.6 H.sub.5                             10      --NHCOCH.sub.3                                                                           --CO(CH.sub.2).sub.3 C.sub.6 H.sub.5                                                             113                                     11      --NHCOCH.sub.3                                                                           4 #STR28##         129                                     12      --NHCOCH.sub.3                                                                           5 #STR29##         125                                     13      --OH       --COOCH.sub.2 C.sub.6 H.sub.5                                                                    76                                      14      --OCOC.sub.2 H.sub.5                                                                     --COOCH.sub.2 C.sub.6 H.sub.5                                                                    86                                      ______________________________________                                    

EXAMPLE 15 1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride,(+)isomer.

A) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride,(+)isomer.

10 g of the compound obtained in the PREPARATION 2.3 are dissolved in 20ml of water, 5 ml of 40% sodium hydroxide are added, the mixture isextracted 3 times with 50 ml of DCM, the organic phase dried over MgSO₄and evaporated to give 9 g of oil. 2.7 g of the oil obtained aredissolved in 50 ml of isopropanol, 2.36 g of 10-camphorsulfonic acid,(+)isomer, are added with the use of heat and the mixture is allowed tocool. The crystals formed (3.86 g) are dissolved in 10% NaOH, themixture is extracted with chloroform, dried over MgSO₄ and evaporated.2.3 g of the product are obtained in the form of an oil of which thehydrochloride is made. The specific rotation of the hydrochloride ismeasured. α!_(D) ²⁵ =+5.5° (c=0.1; methanol).

A second crystallization carried out using 2.12 g of the oil obtainedand 1.84 g of camphorsulfonic acid ((+)isomer) gives 3.27 g of crystalswhich, after basification with sodium hydroxide and extraction, give2.10 g of the expected product in the form of an oil of which thehydrochloride is made. α!_(D) ²⁵ =+6.5° (c=0.1; methanol).

After a third crystallization, the same specific rotation is obtained.The chiral purity, measured by chiral HPLC, is greater than 98%.

B) N-Boc-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-piperidine,(+)isomer.

900 mg of the compound prepared in the preceding stage, 600 mg of TEAand 610 mg of (Boc)₂ O are dissolved in 100 ml of DCM and the mixture isallowed to react under nitrogen, at RT for 30 minutes. The mixture isevaporated, the residue dissolved in AcOEt, washed with a buffer atpH=2, with dilute sodium hydroxide, a solution of NaCl and then driedover MgSO₄ and evaporated to give the expected product in the form of anoil (1.1 g).

C) N-Boc-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)-piperidine,(+)isomer.

1.1 g of the compound obtained in the preceding stage are dissolved at0° C. under nitrogen in 10 ml of DCM, 700 mg of TEA and 325 mg of mesylchloride dissolved in 3 ml of DCM are added. After stirring for 2 hours,the mixture is evaporated, the residual oil taken up in AcOEt, washedwith a buffer solution at pH 2, water, a solution of NaCl and then driedand evaporated. 1.4 g of the expected product are obtained in the formof an oil.

D) N-Boc-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine, (+)isomer.

1.4 g of the compound prepared in the preceding stage and 900 mg of4-phenyl-4-pivaloylaminopiperidine obtained in the PREPARATION 1.1 aredissolved in 25 ml of acetonitrile. 450 mg of K₂ CO₃ are added and themixture is kept stirring for 2 hours at 60° C. The mixture isevaporated, dissolved in AcOEt, washed with a buffer solution at pH 2, adilute solution of NaOH, a solution of NaCl, dried over MgSO₄ andevaporated to give 1.65 g of the expected product in the form of an oil.

E) 3-(3,4-Dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride,(+)isomer.

1.65 g of the compound prepared in the preceding stage and 5 ml of HClat a concentration of 4N in ether are added to 25 ml of DCM. Afterstirring for 1 hour, 1.12 g of the expected compound are obtained.

F) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride,(+)isomer.

1.1 g of the compound obtained in the preceding stage, 800 mg of TEA and252 mg of benzoyl chloride are dissolved in 15 ml of DCM, undernitrogen, at 0° C. After 15 minutes, the mixture is evaporated,dissolved in AcOEt, washed with a dilute solution of HCl , with asolution of NaCl, dried over MgSO₄ and evaporated. The foam obtained ischromatographed on silica, eluting with a DCM/MeOH mixture in a gradientup to 5%. The product obtained is salified by a solution of hydrochloricether. α!_(D) ²⁵ =+24.3 (c=0.1; methanol).

EXAMPLE 16 1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride,(-)isomer.

This compound is obtained as in EXAMPLE 15, using the camphorsulfonicacid, (-)isomer in stage A.

EXAMPLE 17 1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-pivaloylamino-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride,racemate.

This compound is obtained as in EXAMPLE 15 without carrying out theoptical resolution of stage A.

EXAMPLE 18 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl)propyl!piperidinehydrochloride, monohydrate.

A) N-Boc-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-piperidine.

A mixture of 23 g of the compound obtained in the PREPARATION 2.3, 15 gof triethylamine, 16 g of (Boc)₂ O in 100 ml of DCM is kept stirring for1 hour at RT and under a nitrogen atmosphere. The reaction mixture isconcentrated under vacuum, the residue extracted with AcOEt, washed witha buffer solution pH=2, with a 5% solution of NaOH, with a saturatedsolution of NaCl, dried over MgSO₄ and the solvent evaporated undervacuum. 30 g of the expected product are obtained in the form of an oil.

B) N-Boc-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)-piperidine.

A solution of 30 g of the compound obtained in the preceding stage, 15ml of triethylamine in 200 ml of DCM is cooled to 0° C. and a solutionof 9 g of mesyl chloride in 50 ml of DCM is added dropwise under anitrogen atmosphere. The mixture is kept stirring for 2 hours and thesolvent is evaporated under vacuum. The residue is extracted with AcOEt,washed with a buffer solution pH=2, with a 5% solution of NaOH, with asaturated solution of NaCl, dried over MgSO₄ and the solvent evaporatedunder vacuum. 34 g of the expected product are obtained.

C) N-Boc-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidine.

A mixture of 1 g of the compound obtained in the preceding stage, 2 g ofthe compound obtained in the PREPARATION 1.3, 0.6 g of K₂ CO₃ in 15 mlof DMF is heated at 60° C. for 3 hours, then the mixture is keptstirring overnight at RT. AcOEt is added to the reaction mixture, theorganic phase is washed with water, with a saturated solution of NaCl,dried over MgSO₄ and the solvent evaporated under vacuum. The residue ischromatographed on silica H, eluting with the DCM/MeOH mixture (95/5;v/v). 0.78 g of the expected product is obtained.

D) 3-(3,4-Dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride.

2 ml of a saturated solution of HCl in ether are added to a solution of0.78 g of the compound obtained in the preceding stage in 5 ml of DCMand the mixture is kept stirring for 1 hour at RT. The reaction mixtureis evaporated under vacuum and 0.8 g of the expected product is obtainedwhich is used as it is in the next stage.

E) 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate.

A mixture of 0.75 g of the compound obtained in the preceding stage, 0.6ml of triethylamine in 10 ml of DCM is cooled to 0° C. and 0.18 g ofbenzoyl chloride is added under a nitrogen atmosphere. The mixture iskept stirring for 2 hours at 0° C. and the reaction mixture isconcentrated under vacuum. The residue is extracted with AcOEt, washedwith a buffer solution pH=2, with a 5% solution of NaOH, with asaturated solution of NaCl, dried over MgSO₄ and the solvent evaporatedunder vacuum. The residue is chromatographed on silica H, eluting withthe DCM/MeOH mixture (95/5; v/v). The product obtained is taken up inDCM, acidified to pH=1 by addition of hydrochloric ether and evaporatedunder vacuum. 0.5 g of the expected hydrochloride is obtained, m.p.=171°C.

EXAMPLE 19 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate, (+)isomer.

A) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-piperidine,(+)isomer.

A solution of 7.45 g of the compound obtained in stage A of EXAMPLE 15(in the form of a base) in 30 ml of DCM is cooled to -20° C. and 4 ml oftriethylamine are added followed, dropwise, by 2.85 ml of benzoylchloride. The mixture is kept stirring while allowing the temperature torise to RT, then the reaction mixture is washed with a 0.5N solution ofHC₁, with a saturated solution of Na₂ CO₃, the organic phase is driedover MgSO₄ and the solvent evaporated under vacuum. The residue ischromatographed on silica, eluting with the gradient of the DCM/AcOEtmixture from (90/10; v/v) to (80/20; v/v) then with DCM/MeOH (97/3;v/v). 9.40 g of the expected product are obtained.

B) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)-piperidine,(+)isomer.

A solution of 9.4 g of the compound obtained in the preceding stage, 5ml of triethylamine in 50 ml of DCM is cooled to -10° C. and 2.24 ml ofmesyl chloride are added dropwise. The mixture is kept stirring whileallowing the temperature to rise to RT and the solvent is concentratedunder vacuum. The residue is extracted with AcOEt, washed twice withwater, with a saturated solution of NaCl, dried over MgSO₄ and thesolvent evaporated under vacuum. 10 g of the expected product areobtained.

C) 1Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate, (+)isomer.

A mixture of 2 g of the compound obtained in the preceding stage, 4 g of4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate, 1 g ofK₂ CO₃ in 50 ml of acetonitrile and 50 ml of DMF is heated at 100° C.for 2 hours under a nitrogen atmosphere. The reaction mixture isconcentrated under vacuum, the residue extracted with AcOEt, washed withwater, with a 0.5N solution of HCl, with a 10% solution of NaOH, with asaturated solution of NaCl, dried over MgSO₄ and the solvent evaporatedunder vacuum. The residue is chromatographed on silica H, eluting withthe gradient of the DCM/MeOH mixture from (99/1; v/v) to (95/5; v/v).The product obtained is taken up in DCM, acidified to pH=1 by additionof hydrochloric ether and evaporated under vacuum. 1.05 g of theexpected product are obtained. α!_(D) ²⁵ =+21.5°±0.5 (c=1; MeOH).

EXAMPLE 20 1Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate, (-)isomer

A) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride,(-)isomer.

3.8 g of 10-camphorsulfonic acid, (-)isomer, are added to a solution of4.7 g of the compound obtained in the PREPARATION 2.3, in the form of afree base, in 100 ml of isopropanol, and the mixture is refluxed. Aftercooling, crystallization and spinning of the crystals formed (4.90 g),the latter are dissolved in a 10% solution of NaOH, the mixture isextracted with chloroform, dried over MgSO₄ and the solvent evaporatedunder vacuum. 2.7 g of the product are obtained in the form of an oil ofwhich the hydrochloride is made. The specific rotation of thehydrochloride is measured. α!_(D) ²⁵ =-6.5° (c=1; MeOH).

A second crystallization is carried out from 2.6 g of the oil obtained,2.77 g of 10-camphorsulfonic acid, (-)isomer, and 40 ml of isopropanol.After basification with sodium hydroxide, extraction with chloroform,drying over MgSO₄ and evaporation, the expected product is obtained inthe form of an oil of which the hydrochloride is made. 2.4 g of theexpected product are obtained. α!_(D) ²⁵ =-6.8° (c=1; MeOH).

B) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine,(-)isomer.

A solution of 11 g of the compound obtained in the preceding stage (inthe form of a free base), 6 ml of triethylamine in 75 ml of DCM iscooled to -30° C. and 4.2 ml of benzoyl chloride are added dropwise. Themixture is kept stirring while allowing the temperature to rise to RTand then the reaction mixture is poured into water. The mixture isextracted with DCM, the organic phase washed with water, with a 0.5Nsolution of NaOH, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is chromatographed on silica, eluting with thegradient of the DCM/AcOEt mixture from (85/15; v/v) to (75/25; v/v) andthen with DCM/MeOH (97/3; v/v). 10 g of the expected product areobtained.

C) 1Benzoyl-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)piperidine,(-)isomer.

A solution of 10 g of the compound obtained in the preceding stage, 5.5ml of triethylamine in 100 ml of DCM is cooled to -30° C. and 2.4 ml ofmesyl chloride are added dropwise. The mixture is kept stirring whileallowing the temperature to rise to RT and concentrated under vacuum.The residue is extracted with AcOEt, washed twice with water, with asaturated solution of NaCl, dried over MgSO₄ and evaporated undervacuum. 11 g of the expected product are obtained.

D) 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate, (-)isomer.

This compound is prepared according to the procedure described in stageC of EXAMPLE 19 from 0.5 g of the compound obtained in the precedingstage and 0.8 g of 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate. 0.375 g of the expected product is obtained. α!_(D) ²⁵=-21.5°±0.5 (c=1; MeOH).

According to a procedure similar to that described in Example 15, thecompounds according to the invention which are described in Table 2below are prepared:

                                      TABLE 2                                     __________________________________________________________________________                                            (III)                                 6 #STR30##                                                                                                            m.p.                                  Examples                                                                          Ar       R.sub.2      --T--A--Z     ° C.                           __________________________________________________________________________    21  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             --COC.sub.6 H.sub.5                                                                         184 (1)                               22  --C.sub.6 H.sub.5                                                                      --NHCOC.sub.6 H.sub.5                                                                      --COC.sub.6 H.sub.5                                                                         140                                   23  --C.sub.6 H.sub.5                                                                      --NH.sub.2   --COC.sub.6 H.sub.5                                                                         210                                   24  --C.sub.6 H.sub.5                                                                      --NHCOC.sub.2 H.sub.5                                                                      --COC.sub.6 H.sub.5                                                                         137                                   25  --C.sub.6 H.sub.5                                                                      --NHCOCH(CH.sub.3).sub.2                                                                   --COC.sub.6 H.sub.5                                                                         170                                   26  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             --COOCH.sub.2 C.sub.6 H.sub.5                                                               148                                   27  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             --COCH.sub.2 C.sub.6 H.sub.5                                                                175                                   28  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             --CH.sub.2 C.sub.6 H.sub.5                                                                  200                                   29  --C.sub.6 H.sub.5                                                                      7 #STR31##   --COC.sub.6 H.sub.5                                                                         190                                   30  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             8 #STR32##    191                                   31  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             9 #STR33##    199                                   32                                                                                0 #STR34##                                                                             --OH         --COC.sub.6 H.sub.5                                                                         169                                   33  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             1 #STR35##    185                                   34  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             2 #STR36##    213                                   35  --C.sub.6 H.sub.5                                                                      --NCH.sub.3 COiPr                                                                          --COC.sub.6 H.sub.5                                                                         192                                   36  --C.sub.6 H.sub.5                                                                      --NHCOBu     --COC.sub.6 H.sub.5                                                                         170                                   37  --C.sub.6 H.sub.5                                                                      --OCH.sub.3  --COC.sub.6 H.sub.5                                                                         180                                   38  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             3 #STR37##    250                                   39  --C.sub.6 H.sub.5                                                                      --OH         --COC.sub.6 H.sub.5                                                                         205                                   40  --C.sub.6 H.sub.5                                                                      --OH                                                                                       4 #STR38##    160 (1)(2)                            41  --C.sub.6 H.sub.5                                                                      --NHCOCH.sub.3                                                                             5 #STR39##    195                                   __________________________________________________________________________

(1) The preparation of these compounds is described in application EP512901, in Examples 27 and 29.

(2) Dihydrochloride

EXAMPLE 42 1Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-phenyl-(1,2,5,6-tetrahydropyrid-1-yl)propyl!piperidinehydrochloride.

This composition is prepared according to the procedure described abovefrom 4-phenyl-(1,2,5,6-tetrahydrochloride) which is commerciallyavailable.

EXAMPLE 43 1-Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-cyano-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride.

A) 1Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine.

A solution of 16.22 g of the compound obtained in the PREPARATION 2.3,18.2 g of triethylamine in 250 ml of DCM is cooled on an ice bath and asolution of 14.06 g of benzoyl chloride in 10 ml of DCM is addeddropwise. The mixture is kept stirring for 1 hour while allowing thetemperature to rise to RT. The excess benzoyl chloride is removed byaddition of MeOH and the reaction mixture is then concentrated undervacuum. The residue is taken up in MeOH and the solvent evaporated undervacuum. The residue is extracted with ether, washed with water, with a2N solution of HCl, with a 5% solution of NaHCO₃, with a saturatedsolution of NaCl, dried over MgSO₄ and evaporated under vacuum. The1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-benzoyloxypropyl)piperidine thusobtained as an intermediate is dissolved in 150 ml of MeOH, a solutionof 10% NaOH is added, the mixture is heated for 1 hour at 50-60° C. andconcentrated under vacuum. The residue is extracted with ether, washedwith water, with a 2N solution of HCl, with a 5% solution of NaHCO₃,with a saturated solution of NaCl, dried over MgSO₄, and the solventevaporated under vacuum. 18 g of the expected product are obtained inthe form of an oil.

B) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)piperidine.

A solution of 16.8 g of the compound obtained in the preceding stage,5.18 g of triethylamine in 100 ml of DCM is cooled on an ice bath and asolution of 5.40 g of mesyl chloride in 10 ml of DCM is added dropwiseand then the mixture is kept stirring for 30 minutes while allowing thetemperature to rise to RT. The reaction mixture is concentrated undervacuum, the residue is extracted with AcOEt, washed with water, with a2N solution of HCl, with a saturated solution of NaCl, dried over MgSO₄and the solvent evaporated under vacuum. 19.6 g of the expected productare obtained in the form of an oil.

NMR spectrum at 200 MHz in DMSO

1 to 2.35 ppm: m: 8H

3.15 ppm: s: 3H

3.2 to 4.6 ppm: m: 6H

6.8 to 7.8 ppm: m: 8H.

C) 1Benzoyl-3-(3,4-dichlorophenyl)-3-3-(4-cyano-4-phenylpiperid-1-yl)propyl!piperidine hydrochloride.

A mixture of 5.9 g of the compound obtained in the preceding stage, 3 gof 4-cyano-4-phenylpiperidine, 6.9 g of K₂ CO₃ in 20 ml of acetonitrileand 5 ml of DMF is refluxed for 2 hours. After cooling, the reactionmixture is poured into water, extracted with ether, washed with water,dried over MgSO₄ and the solvent evaporated under vacuum. The residue ischromatographed on silica H, eluting with the gradient of DCM/MeOHmixture from (100/1; v/v) to (100/2.5: v/v). The product obtained istaken up in DCM, acidified to pH=1 by addition of hydrochloric ether andevaporated under vacuum. 4.5 g of the expected hydrochloride areobtained after crystallization from the DCM/ether mixture, m.p.=239-241°C.

EXAMPLE 44 3- 3-4-(Aminomethyl)-4-phenylpiperid-1-yl!propyl!-1-benzoyl-3-(3,4-dichlorophenyl)piperidinedihydrochloride, dihydrate.

A mixture of 3.5 g of the compound obtained in EXAMPLE 43, 10 ml of aconcentrated solution of NH₄₀ H, 0.5 g of Raney® nickel, and 50 ml ofEtOH is hydrogenated at RT and at atmospheric pressure. The catalyst isfiltered and the filtrate evaporated under vacuum. The residue isextracted with DCM, washed with water, dried over MgSO₄ and the solventevaporated under vacuum. The residue is taken up in DCM, acidified topH=1 by addition of hydrochloric ether and evaporated under vacuum. 2.8g of the expected product are obtained after crystallization from theDCM/ether mixture, m.p.=174° C.

EXAMPLE 45 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3- 4-(N-ethoxycarbonylamino)methyl!-4-phenylpiperid-1-yl!propyl!-piperidinehydrochloride, hemihydrate.

A solution of 1 g of the compound obtained in EXAMPLE 44, 0.535 g oftriethylamine in 20 ml of DCM is cooled to 0° C. and 0.188 g ofethylchloroformate is added. The mixture is kept stirring for 30 minutesand concentrated under vacuum. The residue is extracted with ether,washed with water, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is chromatographed on silica H, eluting with thegradient of the DCM/MeOH mixture from (100/3; v/v) to (100/5; v/v). Theproduct obtained is taken up in DCM, acidified to pH=1 by addition ofhydrochloric ether and evaporated under vacuum. 0.4 g of the expectedproduct is obtained after crystallization from the DCM/ether mixture,m.p.=135-141° C. (dec).

EXAMPLE 46 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3- 4-(N-propionylamino)methyl!-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate.

0.166 g of propionyl chloride is added to a solution of 0.87 g of thecompound obtained in EXAMPLE 44, 0.3 g of triethylamine in 20 ml of DCMand the mixture is kept stirring for 30 minutes at RT. The mixture isconcentrated under vacuum, the residue is extracted with AcOEt, washedwith water, dried over MgSO₄ and evaporated under vacuum. The residue ischromatographed on silica H, eluting with the gradient of the DCM/MeOHmixture from (100/3; v/v) to (100/5; v/v). The residue is taken up inDCM, acidified to pH=1 by addition of hydrochloric ether and vaporatedunder vacuum. 0.49 g of the expected product is obtained aftercrystallization from the DCM/ether mixture, m.p.=143-149° C. (dec).

EXAMPLE 47 3- 3- 4-(Acetyl-N-methylamino)methyl!-4-phenylpiperid-1-yl!propyl!-1-benzoyl-3-(3,4-dichlorophenyl)piperidinehydrochloride, monohydrate.

A mixture of 1.6 g of the compound obtained in stage B of EXAMPLE 43, 2g of 4- (acetyl-N-methylamino)-methyl!-4-phenylpiperidinep-toluenesulfonate, 2 g of K₂ CO₃ and 4 ml of DMF is heated at 100° C.for 2 hours. After cooling, the reaction mixture is poured into water,extracted with ether, washed with water, dried over Na₂ SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica H, eluting with the DCM/MeOH mixture (100/5; v/v). The productobtained is taken up in DCM, acidified to pH=1 by addition ofhydrochloric ether and evaporated under vacuum. 0.75 g of the expectedhydrochloride is obtained after crystallization from the DCM/ethermixture, m.p.=126° C.

EXAMPLE 48 1Benzoyl-3-(3,4-dichlorophenyl)-3- 3- 4-(N'-ethyl-N-methylureido)methyl!-4-phenylpiperid-1-yl!propyl!-piperidinehydrochloride, hemihydrate.

A mixture of 1.7 g of the compound obtained in stage B of EXAMPLE 43,1.2 g of 4- (N'-ethyl-N-methyl-ureido)methyl!-4-phenylpiperidine, 1 g ofK₂ CO₃ and 5 ml of DMF is heated at 100° C. for 2 hours. After cooling,the reaction mixture is poured into water, extracted with theether/AcOEt mixture, washed with water, dried over Na₂ SO₄ and thesolvent is evaporated under vacuum. The residue is chromatographed onsilica H, eluting with the gradient of the DCM/MeOH mixture from (100/3;v/v) to (100/7; v/v). The product obtained is taken up in DCM, acidifiedto pH=1 by addition of hydrochloric ether and evaporated under vacuum.1.15 g of the expected hydrochloride are obtained after crystallizationfrom the DCM/ether mixture, m.p.=160° C.

EXAMPLE 49 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3- 4-(N',N'-diethyl-N-methylureido)methyl!-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, hemihydrate.

This compound is prepared according to the procedure described inEXAMPLE 48 from 2 g of the compound obtained in stage B of EXAMPLE 43,2.85 g of 4- (N',N'-diethyl-N-methylureido)methyl!-4-phenylpiperidinep-toluenesulfonate, 2.5 g of K₂ CO₃ and 4 ml of DMF. 0.9 g of theexpected hydrochloride is obtained after crystallization from theDCM/ether mixture, m.p.=117-132° C. (dec).

EXAMPLE 50 1Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(piperid-1-yl)-4-phenylpiperid-1-yl!propyl!piperidine dihydrochloride,dehydrate.

1.7 g of 4-phenyl-4-(piperid-1-yl)piperidine dihydrochloride dihydrateare dissolved in a 40% solution of NaOH, the mixture is extracted withDCM, dried over MgSO₄ and the solvent evaporated under vacuum. Theresidue is taken up in 20 ml of DMF, 1.25 g of the compound obtained instage B of EXAMPLE 43 are added and the mixture is heated at 100° C. for2 hours. After cooling, the reaction mixture is diluted with DCM, theorganic phase is washed with water, with a 1N solution of HCl, with a 5%solution of NaOH, with a saturated solution of NaCl, dried over MgSO₄and the solvent evaporated under vacuum. The residue is chromatographedon silica H, eluting with the DCM/MeOH mixture (95/5; v/v). The productobtained is taken up in DCM, acidified to pH=1 by addition ofhydrochloric ether and evaporated under vacuum. 1.2 g of the expectedproduct are obtained, m.p.=192° C.

EXAMPLE 51 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(formylamino)-4-phenylpiperid-1-yl!propyl!piperidine hydrochloride,monohydrate.

0.55 g of 4-(formylamino)-4-phenylpiperidine hydrochloride is dissolvedin water, the mixture is alkalinized by addition of concentrated NaOH,extracted with DCM, dried over MgSO₄ and the solvent evaporated undervacuum. The residue is taken up in 20 ml of acetonitrile, 0.9 g of thecompound obtained in stage B of EXAMPLE 43 and 1 g of K₂ CO₃ are addedand the mixture is refluxed for 2 hours and 30 minutes. The mixture isconcentrated under vacuum, the residue extracted with AcOEt, washed withwater, with a 5% solution of NaOH, dried over MgSO₄ and the solventevaporated under vacuum. The residue is chromatographed on silica H,eluting with DCM then with the DCM/MeOH mixture (90/10; v/v). Theproduct obtained is taken up in DCM, acidified by addition ofhydrochloric ether and evaporated under vacuum. 0.53 g of the expectedproduct is obtained after crystallization from isoether.

NMR spectrum at 200 MHz in DMSO

1.1 to 2.65 ppm: m: 12H

2.7 to 4.5 ppm: m: 10H

7.0 to 7.7 ppm: m: 13H

8.0 ppm: s: 1H

8.4 ppm: s: 1H 10.5 ppm: bs: 1H.

EXAMPLE 52 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(cyclopropylcarbonylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate.

0.370 g of 4-(cyclopropylcarbonylamino)-4-phenylpiperidine hydrochlorideis dissolved in water, the mixture is alkalinized by addition ofconcentrated NaOH, extracted with DCM, dried over MgSO₄ and the solventevaporated under vacuum. The residue is taken up in 10 ml of DMF, 0.655g of the compound obtained in stage B of EXAMPLE 43 and 0.192 g of K₂CO₃ are added and the mixture is heated at 80° C. for 30 minutes. Afterstirring overnight at RT, the reaction mixture is poured into water,extracted with AcOEt, washed twice with water, with a saturated solutionof NaCl, dried over MgSO₄ and the solvent evaporated under vacuum. Theresidue is chromatographed on silica, eluting with DCM, and then withthe DCM/MeOH mixture (95/5; v/v). The product obtained is taken up inDCM, acidified to pH=1 by addition of hydrochloric ether and evaporatedunder vacuum. 0.27 g of the expected product is obtained.

NMR spectrum at 200 MHz in DMSO

0.6 ppm: mt: 4H

1.0 to 2.7 ppm: m: 13H

2.75 to 4.5 ppm: m: 10H

7.0 to 7.9 ppm: m: 13H

8.4 ppm: s: 1H

10 ppm: bs: 1H.

EXAMPLE 53 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-methoxycarbonyl-4-phenylpiperid-1-yl!propyl!piperidine hydrochloride,hemihydrate.

A mixture of 0.9 g of 4-methoxycarbonyl-4-phenylpiperidinep-toluenesulfonate, 0.91 g of the compound obtained in stage B ofEXAMPLE 43, 1.06 g of K₂ CO₃ in 5 ml of DMF and 5 ml of acetonitrile isrefluxed for 3 hours. The reaction mixture is poured into water,extracted with AcOEt, washed twice with water, with a saturated solutionof NaCl, dried over MgSO₄ and the solvent evaporated under vacuum. Theresidue is chromatographed on silica H, eluting with DCM, and then withthe DCM/MeOH mixture (97/3; v/v). The product obtained is taken up inAcOEt, acidified by addition of hydrochloric ether and evaporated undervacuum. 0.54 g of the expected product is obtained after crystallizationfrom the acetone/ether mixture, m.p.=123-125° C.

EXAMPLE 54 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(N,N-diethylcarbamoyl)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate.

This compound is prepared according to the procedure described inEXAMPLE 53 from 1.7 g of 4-(N,N-diethylcarbamoyl)-4-phenylpiperidinetrifluoroacetate, 1.77 g of the compound obtained in stage B of EXAMPLE43, 2.08 g of K₂ CO₃, 5 ml of DMF and 5 ml of acetonitrile. 1.1 g of theexpected product are obtained, m.p.=124-126° C.

EXAMPLE 55 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(N-methoxy-N-methylcarbamoyl)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, hemihydrate.

This compound is prepared according to the procedure described inEXAMPLE 53 from 1.1 g of4-(N-methoxy-N-methylcarbamoyl)-4-phenylpiperidine, 1.73 g of thecompound obtained in stage B of EXAMPLE 43, 1.52 g of K₂ CO₃, 5 ml ofDMF and 5 ml of acetonitrile. 0.99 g of the expected product isobtained, m.p.=155-157° C.

EXAMPLE 56 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(methylsulfonamido)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, hemihydrate.

1.6 g of 4-(methylsulfonamido)-4-phenylpiperidine hydrochloride aredissolved in a minimum of a 40% solution of sodium hydroxide, themixture is extracted with DCM, the organic phase dried over MgSO₄ andthe solvent evaporated under vacuum. The residue is dissolved in 25 mlof DMF, 1.29 g of the compound obtained in stage B of EXAMPLE 43 areadded and the mixture is heated, under a nitrogen atmosphere, at 80° C.for 2 hours. The reaction mixture is poured into water, the precipitateformed spun and washed with water. The precipitate is dissolved in DCM,the organic phase is washed twice with water, dried over MgSO₄ and thesolvent evaporated under vacuum. The residue is chromatographed onsilica H, eluting with DCM, and then with the DCM/MeOH mixture (95/5;v/v). The product obtained is taken up in DCM, acidified by addition ofhydrochloric ether and evaporated under vacuum. 0.7 g of the expectedproduct is obtained, m.p.=210° C.

EXAMPLE 57 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(methanesulfonyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!-piperidinehydrochloride, hemihydrate.

A mixture of 0.79 g of4-(methanesulfonyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate,0.70 g of the compound obtained in stage B of EXAMPLE 43, 0.80 g of K₂CO₃ and 10 ml of acetonitrile is refluxed for 3 hours. The reactionmixture is concentrated under vacuum, the residue taken up in water,extracted with AcOEt, washed with a 5% solution of NaOH, dried overMgSO₄ and the solvent evaporated under vacuum. The residue ischromatographed on silica is H, eluting with DCM, and then with theDCM/MeOH mixture (95/5; v/v). The product obtained is taken up in DCM,acidified by addition of hydrochloric ether and evaporated under vacuum.0.71 g of the expected product is obtained after crystallization fromether.

NMR spectrum at 200 MHz in DMSO

1.0 to 2.45 ppm: m: 15H

2.45 to 4.50 ppm: m: 13H

7.0 to 7.9 ppm: m: 13H

10.75 ppm: s: 1H.

EXAMPLE 58 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-(propionyloxy)-4-phenylpiperid-1-yl!propyl!piperidine hydrochloride,hemihydrate.

A solution of 0.95 g of the compound obtained in EXAMPLE 39, 0.4 ml oftriethylamine in 50 ml of DCM is cooled to 0° C., 0.15 ml of propionylchloride is added dropwise and the mixture is kept stirring whileallowing the temperature to rise to RT. The reaction mixture isconcentrated under vacuum and the residue is chromatographed on silica,eluting with the gradient of the DCM/MeOH mixture from (99/1; v/v) to(97/3; v/v). The product obtained is taken up in DCM, acidified byaddition of hydrochloric ether and evaporated under vacuum. 0.5 g of theexpected product is obtained.

NMR spectrum at 200 MHz in DMSO

1.0 ppm: t: 3H

1.15 to 2.0 ppm: m: 6H

2.0 to 2.8 ppm: m: 8H

2.9 to 4.6 ppm: m: 10H

7.1 to 7.9 ppm: m: 13H

10.2 ppm: bs: 1H

EXAMPLE 59 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3- 4-(spiro(phthalide-3)piperid-1-yl!propyl!piperidine hydrochloride, monohydrate.

A mixture of 1.4 g of 4-spiro(3-phthalide)-piperidine hydrochloride,0.715 g of potassium tert-butoxide and 15 ml of DMF is stirred for 5minutes. 2.5 g of the compound obtained in stage B of EXAMPLE 43, 2 g ofK₂ CO₃ are then added and the mixture is heated at 100° C. for 45minutes and kept stirring overnight at RT. The reaction mixture isdiluted by addition of AcOEt, the organic phase is washed with a buffersolution pH=2, with a 5% solution of NaOH, with a saturated solution ofNaCl, dried over MgSO₄ and evaporated under vacuum. The residue ischromatographed on silica H, eluting with a gradient of the DCM/MeOHmixture from (99/1; v/v) to (95/5; v/v). The product obtained is takenup in DCM, acidified by addition of hydrochloric ether and evaporatedunder vacuum. 0.77 g of the expected product is obtained, m.p.=165° C.

The compounds according to the invention which are described in TABLE 3below are prepared according to the procedures described in the EXAMPLESabove.

                                      TABLE 3                                     __________________________________________________________________________                                        (III)                                     6 #STR40##                                                                                                      Solvate                                                                       m.p. ° C.                            Examples                                                                           Ar   R.sub.2          --T--A--Z                                                                            or NMR                                      __________________________________________________________________________    60 (a)                                                                             --C.sub.6 H.sub.5                                                                  7 #STR41##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O NMR                           61 (a)                                                                             --C.sub.6 H.sub.5                                                                  8 #STR42##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O NMR                           62 (b)                                                                             --C.sub.6 H.sub.5                                                                  9 #STR43##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O NMR                             63 (b)                                                                             --C.sub.6 H.sub.5                                                                  0 #STR44##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O NMR                             64 (c)                                                                             --C.sub.6 H.sub.5                                                                  1 #STR45##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O 130-135                       65 (d)                                                                             --C.sub.6 H.sub.5                                                                  2 #STR46##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 155-157                         66 (d)                                                                             --C.sub.6 H.sub.5                                                                  3 #STR47##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 130-132                         67 (d)                                                                             --C.sub.6 H.sub.5                                                                  4 #STR48##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 144-146                         68 (a)                                                                             --C.sub.6 H.sub.5                                                                  5 #STR49##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 180                             69 (d)                                                                             --C.sub.6 H.sub.5                                                                  --CH.sub.2 --OH  --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O                                                                 146-149                                     70 (d)                                                                             --C.sub.6 H.sub.5                                                                  6 #STR50##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O 133-135                       71 (d)                                                                             --C.sub.6 H.sub.5                                                                  7 #STR51##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 135                             72 (d)                                                                             --C.sub.6 H.sub.5                                                                  8 #STR52##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O 135                           73 (d)                                                                             --C.sub.6 H.sub.5                                                                  9 #STR53##       --COC.sub.6 H.sub.5                                                                  0.5 H.sub.2 O 245-248                       74 (d)                                                                             --C.sub.6 H.sub.5                                                                  0 #STR54##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 140-142                         75 (d)                                                                             --C.sub.6 H.sub.5                                                                  1 #STR55##       --COC.sub.6 H.sub.5                                                                  1 H.sub.2 O 140-142                         __________________________________________________________________________

(a) this compound is prepared according to the procedure described inEXAMPLE 47

(b) this compound is prepared according to the procedure described inEXAMPLE 52

(c) this compound is prepared according to the procedure described inEXAMPLE 43 stage C

(d) this compound is prepared according to the procedure described inEXAMPLE 53.

NMR spectrum at 200 MHz in DMSO of the compound of

EXAMPLE 60

0.85 ppm: st: 3H

1.0 to 2.5 ppm: m: 12H

2.5 to 4.5 ppm: m; 12H

7.0 to 7.9 ppm: m: 13H

8.3 to 8.6 ppm: ss: 1H

9.2 to 11.0 ppm: ss: 1H

NMR spectrum at 200 MHz in DMSO of this compound of

EXAMPLE 61

0.7 to 2.3 ppm: m: 13H

2.6 to 4.6 ppm: m: 15M

7.0 to 7.9 ppm: m: 13H

10.3 ppm; bs: 1H

NMR spectrum at 200 MHz in DMSO of the compound of

EXAMPLE 62

1.4 to 3.1 ppm: m: 19H

3.15 to 4.9 ppm: m: 10H

7.1 to 7.8 ppm: m: 13H

7.95 ppm: s: 1H

10.0 ppm: bs: 1H

NMR spectrum at 200 MHz in DMSO of the compound of

EXAMPLE 63

0.8 to 2.7 ppm: m: 23H

2.75 to 4.6 ppm: m: 10H

7.0 to 8.0 ppm: m: 13H

8.0 ppm: s: 1H

10.2 ppm: bs: 1H

EXAMPLE 76 1-Benzoyl-3-(3,4-dichlorophenyl)-3- 3-4-hydroxy-4-(2-methoxyphenyl)piperid-1-yl!propyl!piperidinehydrochloride, 1.5-hydrate.

A mixture of 1.80 g of 4-hydroxy-4-(2-methoxyphenyl)piperidine, 1.92 gof the compound obtained in stage B of EXAMPLE 43 in 10 ml of DMF isheated at 80° C. for 2 hours. The reaction mixture is poured into water,the precipitate formed spun and washed with water. The precipitate isdissolved in chloroform, the organic phase is washed with water, with abuffer solution pH=2 and dried over MgSO₄ and the solvent evaporatedunder vacuum. The residue is chromatographed on silica H, eluting withthe gradient of the DCM/MeOH mixture from (99/1; v/v) to (97/3; v/v).The product obtained is taken up in hydrochloric ether and theprecipitate formed is spun. 0.7 g of the expected product is obtained,m.p.=180° C.

EXAMPLE 77 1-(4-Iodobenzoyl)-3-(3,4-dichlorophenyl)-3- 3-4-(acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!piperidinehydrochloride, monohydrate, (+)isomer.

A)1-(4-Iodobenzoyl)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine,(+)isomer.

6.5 ml of triethylamine are added at RT to a mixture of 5 g of thecompound obtained in stage A of EXAMPLE 15, 3.9 g of 4-iodobenzoic acidin 100 ml of DCM, followed by 8.2 g of BOP and the mixture is keptstirring for 15 minutes at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up in ether, the organic phase iswashed with water, with a 1N solution of NaOH, with water, with a 1Nsolution of HCl, with a saturated solution of NaCl, dried over MgSO₄ andthe solvent evaporated under vacuum. The residue is chromatographed onsilica, eluting with DCM and then with the DCM/AcOEt mixture (50/50;v/v) and then with AcOEt. 8.5 g of the expected product are obtained.

B)1-(4-Iodobenzoyl)-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl)piperidine,(+)isomer.

A solution of 8.5 g of the compound obtained in the preceding stage, 2.7ml of triethylamine in 150 ml of DCM is cooled to 0° C. and 1.5 ml ofmesyl chloride are added dropwise. The mixture is kept stirring whileallowing the temperature to rise to RT and the mixture is concentratedunder vacuum. The residue is extracted with ether, the organic phase iswashed twice with water, dried over MgSO₄ and the solvent evaporatedunder vacuum. 10 g of the expected product are obtained.

C) 1-(4-Iodobenzoyl)-3-(3,4-dichlorophenyl)-3- 3-4-acetyl-N-methylamino)-4-phenylpiperid-1-yl!propyl!-piperidinehydrochloride, monohydrate, (+)isomer.

A mixture of 10 g of the compound obtained in the preceding stage, 8.2 gof 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate, 9.3 gof K₂ CO₃ in 80 ml of DMF is heated at 80° C. for 1 hour. Then 4 g of4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluene sulfonate areadded to the reaction mixture and the heating is continued at 80° C. for2 hours. After cooling, the reaction mixture is poured into ice-coldwater, the precipitate formed is spun and washed with water. Theprecipitate is dissolved in DCM, the organic phase is dried over MgSO₄and the solvent evaporated under vacuum. The residue is chromatographedon silica H, eluting with DCM, then with the DCM/MeOH mixture (95/5;v/v). The product obtained is taken up in DCM, acidified to pH=1 byaddition of hydrochloric ether and evaporated under vacuum. 9.2 g of theexpected product are obtained after crystallization from ether,m.p.=172° C. (dec). α!_(D) ²⁵ =+27.2° (c=1; MeOH)

We claim:
 1. A compound of formula (I): ##STR56## and salts thereof, inwhich:Ar represents a pyrid-2-yl or a phenyl which is unsubstituted orsubstituted by a halogen, a methyl or a (C₁ -C₄) alkoxy: R₁ represents amethyl group; R₁₁ represents hydrogen; R₂ represents a hydroxyl; a (C₁-C₇)alkoxy; a (C₁ -C₇)acyloxy; a cyano; an --NR₆ R₇ group; an --NR₃ COR₄group; an --NR₃ COOR₈ group; an --NR₃ SO₂ R₉ group; an --NR₃ CONR₁₀ R₁₂group; a (C₁ -C₇)acyl group; a (C₁ -C₇)alkoxycarbonyl; a --CONR₁₀ R₁₂group; a --CH₂ OH group; a (C₁ -C₇)alkoxymethyl; a (C₁-C₇)acyloxymethyl; a (C₁ -C₇)alkylaminocarbonyloxymethyl; a --CH₂ NR₁₃R₁₄ group; a --CH₂ NR₃ COR₄ group; a --CH₂ NR₃ COOR₈ group; a --CH₂ NR₃SO₂ R₉ group; a --CH₂ NR₃ CONR₁₀ R₁₂ group; or R₂ constitutes a doublebond between the carbon atom to which it is attached and the adjacentcarbon atom of the piperidine ring; or Ar and R₂, together with thecarbon atom to which they are attached, constitute a group of formula:##STR57## R₃ represents a hydrogen or a (C₁ -C₄)alkyl; R₄ represents ahydrogen, a (C₁ -C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by one or moremethyls; or R₃ and R₄ together represent a --(CH₂)_(n) -- group; n is 3or 4: T represents a methylene, a carbonyl, a --COO-- group, a --CONR₅-- group; A represents a direct bond, a methylene, an ethylene, apropylene, a vinylene; or --T--A-- represents --SO₂ --; Z represents aphenyl which is unsubstituted or substituted one or several times by ahalogen, a (C₁ -C₄)alkyl, a (C₁ -C₄)alkoxy, or a nitro group; R₅represents hydrogen or (C₁ -C₄)alkyl; R₆ and R₇ each representindependently a hydrogen or a (C₁ -C₇)alkyl; or R₇ represents a (C₃-C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₆ and R₇, together withthe nitrogen atom to which they are attached, constitute a heterocycleselected from the group consisting of azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine and perhydroazepine; R₈,represents a (C₁ -C₇)alkyl or a phenyl; R₉ represents a (C₁ -C₇)alkyl;an amino which is free or substituted by one or two (C₁ -C₇)alkyls; aphenyl which is unsubstituted or substituted once or several times by asubstituent selected from the group consisting of a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl,a (C₁ -C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a cyano, a nitro,and an amino which is free or substituted by one or two (C₁ -C₇)alkyls,said substituents being identical or different; R₁₀ and R₁₂ eachrepresent independently a hydrogen or a (C₁ -C₇)alkyl; or R₁₂ representsa (C₃ -C₇)cycloalkyl, a (C₃ -C₇)cycloalkylmethyl, a hydroxyl, a (C₁-C₄)alkoxy, a benzyl or a phenyl; or R₁₀ and R₁₂, together with thenitrogen atom to which they are attached, constitute a heterocycleselected from the group consisting of azetidine, pyrrolidine,piperidine, morpholine, thiomorpholine and perhydroazepine; R₁₃ and R₁₄each represent independently a hydrogen or a (C₁ -C₇)alkyl; or R₁₄represents a (C₃ -C₇)cycloalkylmethyl or a benzyl; provided that when Aris a phenyl group, and T--A--Z is the benzoyl group, R₂ is not ahydroxyl group or a C₁ C₇ alkoxy and that when Ar is a phenyl group, andT--A--Z is unsubstituted benzyloxy-carbonyl, R₂ is not an acetamidogroup.
 2. A compound of formula (II): ##STR58## or a salt thereof, inwhich:Ar is as defined in claim 1; R₂ is an acetamido, a propionylamino,a butylamino, an isobutyrylamino, an acetyl-N-methylamino, apropionyl-N-methylamino, a butyryl-N-methylamino, anisobutyryl-N-methylamino; and T--A--Z represents a benzyloxycarbonylwhich is unsubstituted or substituted on the phenyl by a chlorine or anitro provided that when Ar is a phenyl group, and T--A--Z isunsubstituted benzyloxy-carbonyl, R₂ is not an acetamido group.
 3. Acompound of formula (II): ##STR59## and salts thereof, in which:Ar, Z, Tand A are as defined in claim 1, and R₂ represents a (C₅ -C₇)alkoxy, a(C₅ -C₇)acyloxy, an --NR₃ COR₄ group with R₄ other than (C₁ -C₆)alkylwhen R₃ is hydrogen, an --NR₆ R₇ group with R₆ and R₇ other than H or(C₁ -C₄)alkyl, an --NR₃ COOR₈ group, an --NR₃ SO₂ R₉ group, an --NR₃CONR₁₀ R₁₂ group, a (C₅ -C₇)acyl, a (C₅ -C₇)alkoxycarbonyl, a --CONR₁₀R₁₂ group, a (C₁ -C₇)alkoxymethyl, a (C₁ -C₇)acyloxymethyl, a (C₁-C₇)alkylaminocarbonyloxymethyl, a --CH₂ NR₁₃ R₁₄ group with R₁₃ and R₁₄other than hydrogen, a --CH₂ NR₃ COR₄ group with R₄ other than (C₁-C₃)alkyl when R₃ is hydrogen, a --CH₂ NR₃ COOR₈ group, a CH₂ NR₃ SO₂ R₉group, or a --CH₂ NR₃ CONR₁₀ R₁₂ group.
 4. A compound of formula (II):##STR60## and salts thereof, in which:Ar, Z, R₂ and A are as defined inclaim 1; and T represents a methylene, or a --CONR₅ -- group with R₅other than hydrogen.
 5. A compound of formula (II): ##STR61## and saltsthereof, in which:Ar represents a pyrid-2-yl or a phenyl which isunsubstituted or substituted by a halogen, a methyl or a (C₁ -C₄)alkoxy;R₂ represents a hydroxyl; a (C₁ -C₇)alkoxy; a (C₁ -C₇)acyloxy; a cyano;an --NR₆ R₇ group; an --NR₃ COR₄ group; an --NR₃ COOR₈ group; an --NR₃SO₂ R₉ group; an --NR₃ CONR₁₀ R₁₂ group; a (C₁ -C₇)acyl group; a (C₁-C₇)alkoxycarbonyl; a --CONR₁₀ R₁₂ group; a --CH₂ OH group; a (C₁-C₇)alkoxymethyl; a (C₁ -C₇)acyloxymethyl; a (C₁-C₇)alkylaminocarbonyloxymethyl; a --CH₂ NR₁₃ R₁₄ group; a --CH₂ NR₃COR₄ group; a --CH₂ NR₃ COOR₈ group; a --CH₂ NR₃ SO₂ R₉ group; a --CH₂NR₃ CONR₁₀ R₁₂ group; or R₂ constitutes a double bond between the carbonatom to which it is attached and the adjacent carbon atom of thepiperidine ring; or Ar and R₂, together with the carbon atom to whichthey are attached, constitute a group of formula: ##STR62## R₃represents a hydrogen or a (C₁ -C₄)alkyl; R₄ represents a hydrogen, a(C₁ -C₇)alkyl, a phenyl, a benzyl, a pyridyl or a (C₃ -C₇)cycloalkylwhich is unsubstituted or substituted by one or more methyls; or R₃ andR₄ together represent a --(CH₂)_(n) -- group; n is 3 or 4; --T--A--represents a --SO₂ -- group Z represents a phenyl which is unsubstitutedor substituted one or several times by a halogen, a (C₁ -C₄)alkyl, a (C₁-C₄)alkoxy, or a nitro group; R₅ represents hydrogen or a (C₁ -C₄)alkyl;R₆ and R₇ each represent independently a hydrogen or a (C₁ -C₇)alkyl; orR₇ represents a (C₃ -C₇)cycloalkylmethyl, a benzyl or a phenyl; or R₆and R₇, together with the nitrogen atom to which they are attached,constitute a heterocycle selected from the group consisting ofazetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine; R₈ represents a (C₁ -C₇)alkyl or a phenyl; R₉represents a (C₁ -C₇)alkyl; an amino which is free or substituted by oneor two (C₁ -C₇)alkyls; a phenyl which is unsubstituted or substitutedonce or several times by a substituent selected from the groupconsisting of a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls, said substituents beingidentical or different; R₁₀ and R₁₂ each represent independently ahydrogen or a (C₁ -C₇)alkyl; or R₁₂ represents a (C₃ -C₇)cycloalkyl, a(C₃ -C₇)cycloalkylmethyl, a hydroxyl, a (C₁ -C₄)alkoxy, a benzyl or aphenyl; or R₁₀ and R₁₂, together with the nitrogen atom to which theyare attached, constitute a heterocycle selected from the groupconsisting of azetidine, pyrrolidine, piperidine, morpholine,thiomorpholine and perhydroazepine; R₁₃ and R₁₄ each representindependently a hydrogen or a (C₁ -C₇)alkyl; or R₁₄ represents a (C₃-C₇)cycloalkylmethyl or a benzyl; in the form of a racemate or a (+) or(-) enantiomer.
 6. A compound of formula (II): ##STR63## and saltsthereof, in which:Ar represents a phenyl; R₂ represents a hydroxyl, a(C₁ -C₇)alkoxy, or an --NR₃ COR₄ group; R₃ represents hydrogen; R₄represents a (C₁ -C₄)alkyl; T represents a carbonyl or a --COO-- group;A represents a direct bond, a methylene, an ethylene, a propylene, or avinylene; and Z represents a phenyl which is unsubstituted ormonosubstituted by a halogen, a (C₁ -C₄)alkoxy, or a nitro group;provided that when T--A--Z is a benzoyl group, R₂ is not a hydroxylgroup and when T--A--Z is unsubstituted benzyloxy-carbonyl, R₂ is not anacetamide group.
 7. A pharmaceutical composition containing, as activeprinciple, a NK3 inhibitory effective amount of a compound as claimed inclaim 1, together with at least one pharmaceutically acceptable carrier.8. A pharmaceutical composition containing, as active principle, a NK3inhibitory effective amount of a compound as claimed in claim 2,together with at least one pharmaceutically acceptable carrier.
 9. Apharmaceutical composition containing, as active principle, a NK3inhibitory effective amount of a compound as claimed in claim 3,together with at least one pharmaceutically acceptable carrier.
 10. Apharmaceutical composition containing, as active principle, a NK3inhibitory effective amount of a compound as claimed in claim 4,together with at least one pharmaceutically acceptable carrier.
 11. Apharmaceutical composition containing, as active principle, a NK3inhibitory effective amount of a compound as claimed in claim 5,together with at least one pharmaceutically acceptable carrier.
 12. Apharmaceutical composition containing, as active principle, a NK3inhibitory effective amount of a compound as claimed in claim 6,together with at least one pharmaceutically acceptable carrier.
 13. Apharmaceutical composition according to claim 7 in the form of a dosageunit.
 14. A pharmaceutical composition according to claim 13, containingfrom 0.5 to 1000 mg of active principle.
 15. A pharmaceuticalcomposition according to claim 14, containing from 2.5 to 250 mg ofactive principle.